Significant detection of new germline pathogenic variants in Australian Pancreatic Cancer Screening Program participants

Murali, Krithika; Dwarte, Tanya M.; Nikfarjam, Mehrdad; Tucker, Katherine M.; Vaughan, Rhys B.; Efthymiou, Marios; Collins, Allison; Spigelman, Allan D.; Salmon, Lucinda; Johns, Amber L.; Williams, David B.; Delatycki, Martin B.; John, Thomas; Stoita, Alina

doi:10.1186/s13053-021-00190-1

Hereditary Cancer in Clinical Practice

Table 2 All germline pathogenic variants (PV) and variants of uncertain significance (VUS) identified in screening participants

From: Significant detection of new germline pathogenic variants in Australian Pancreatic Cancer Screening Program participants

Gene	HGVS Nomenclature	Molecular consequence	Number of participants	PHx Cancer	FHx PDAC
ATM	c.1444A > C	VUS	n = 1 Female	Dx 47 breast	1FDR;1SDR
BRCA1	c.14C > T ^a	VUS	n = 1 Female^a	–	2FDR; 1SDR
	c.2475delC	Pathogenic; Frameshift/Truncating mutation	n = 1 Female^b	Dx 42/54 breast; Dx 48 fallopian tube	1FDR
BRCA2	c.250C > T	Pathogenic; Nonsense	n = 1 Female	Dx 49 breast	1FDR
	c.750_753del4	Pathogenic; Deletion	n = 1 Female	–	2SDR
	c.971G > C^a	VUS	n = 1 Female^a	–	2FDR; 1SDR
	c.2808_2811del	Pathogenic; Frameshift/Truncating mutation	n = 1 Male (at 50% risk)	–	2FDR (siblings)
	c.3847_3848delGT	Pathogenic; Frameshift/Truncating mutation	n = 1 Male	–	2FDR
	c.4405_4409del	Pathogenic; Frameshift/Truncating mutation	n = 1 Female	Dx 53 follicular thyroid; Dx 63 breast	1FDR; 1TDR
	c.4478_4481del	Pathogenic; Frameshift/Truncating mutation	n = 1 Female	Dx 37/49 breast	1FDR
	c.4544del	Pathogenic; Frameshift/Truncating mutation	n = 1 Male	Dx 42/43 melanoma	1FDR
	c.4587dupG	Pathogenic; Frameshift/Truncating mutation	n = 1 Male	–	5FDR
	c.5238dup	Pathogenic; Nonsense	Kindred 1
			n = 1 Female	Dx 57/58 breast	1FDR; 1SDR
			Kindred 2
			n = 1 Female^c	Dx 55 PDAC on study; Dx56 CRC	1FDR
			n = 1 Female	-	2FDR
			n = 1 Male	-	2FDR
	c.5303-5304delTT	Pathogenic; Frameshift/Truncating mutation	n = 1 Female	–	1FDR
	c.5681dupA	Pathogenic; Truncating mutation	Kindred 1
			n = 1 Female^c	Dx 48 PDAC on study; Dx49 gastric	1FDR; 1SDR
			n = 2 Males	-	2FDR^c; 1SDR
			n = 1 Female	-	1FDR; 2SDR^c
			n = 1 Female (at 50% risk)	-	2FDR^c; 1SDR
	c.5682C > G	Pathogenic; Truncating mutation	n = 1 Male	Dx 58 liver	1FDR
	c.5946del (Jewish founder)	Pathogenic; Frameshift/Truncating mutation	Kindred 1
			n = 1 male	Dx 64 prostate	1FDR
			n = 1 female	-	1FDR
			n = 1 female	-	1SDR
			Kindred 2
			n = 1 female	Dx 45 DCIS	1SDR
			Kindred 3
			n = 1 Female^b	Dx 42/54 breast; Dx 48 fallopian tube	1FDR
			Kindred 4
			n = 1 Female	-	1SDR; 3TDR
			n = 1 Female	Dx 65 ovarian	1SDR; 3TDR
			Kindred 5
			n = 1 Male	-	1FDR
			Kindred 6
			n = 1 female	-	1TDR
			n = 2 males	-	1SDR
			Kindred 7
			n = 1 male	Dx 55 brain; Dx 60 prostate	1FDR; 1SDR
			Kindred 8
			n = 1 Male	-	1FDR
			n = 1 Female	Dx 34 CRC	1FDR
	c.6405_6409delCTTAA	Pathogenic; Frameshift/Truncating mutation	n = 1 Male	–	1FDR
	c.7505G > A	VUS	n = 1 Female	Dx 32 breast	1FDR; 1SDR
	c.7757G > A	Pathogenic; Nonsense	n = 1 Male	–	1FDR
	c. 7806-2A > G	Pathogenic; Splice acceptor	n = 1 Male	–	1FDR
	c.7976 + 5G > C	Likely pathogenic; Splicing disruptor	n = 1 Female	–	1SDR
	c.7977-1G > C	Pathogenic; Splice acceptor	n = 1 Male	–	1SDR
	c.7988A > T	Pathogenic; Missense	n = 1 Female	Dx 49 breast	1FDR
	c.8167G > C	Pathogenic; Missense	n = 1 Female	Dx 39 breast	1FDR
	c.8575del	Pathogenic; Frameshift/Truncating mutation	Kindred 1
			n = 1 Male	Dx 75 RCC	1FDR
			n = 1 Female	Dx 62 breast	1FDR
			n = 1 Male	-	1SDR
			Kindred 2
			n = 1 Female	-	1FDR
	c.9154C > T	Pathogenic; Missense	n = 1 Female	–	1FDR; 1SDR
	c.9294C > G	Pathogenic; Truncating mutation	Kindred 1
			n = 1 Male	-	1FDR
			n = 1 Female	Dx 46 breast	1FDR
	c.9371A > T	Pathogenic; Missense	n = 1 Female	Dx 44 breast	1SDR
	c.9924C > G	Pathogenic; Truncating mutation	Kindred 1
			n = 1 Female	Dx 43 breast	2TDR
n = 1 Female			Dx 33/40 breast	1SDR; 1TDR
Exon 14–16 deletion	Pathogenic; Deletion	n = 1 Male	–	1FDR
CDKN2A	c.47 T > G p.(Leu16Arg)	Pathogenic; Missense	n = 1 Female	Dx 45 melanoma	1FDR; 1SDR
	c.95 T > C	Pathogenic; Missense	Kindred 1
			n = 1 Female	-	3FDR
			Kindred 2
			N = 1 Male n = 1	Dx 30 melanoma	2SDR
			Female	Dx 21 melanoma	2SDR
			n = 1 Female	-	1FDR; 1SDR
MLH1	c.1758delC	Pathogenic; Truncating mutation	n = 1 Male	Dx 37 BCC; Dx 40 CRC	1FDR
PALB2	c.487_488del	Pathogenic; Frameshift/Truncating mutation	Kindred 1
			n = 1 Female	Dx 49 breast	1FDR; 2SDR
			n = 1 Female (at 50% risk)	-	1FDR; 2SDR
			n = 1 Male	-	1FDR; 2SDR
	c.2257C > T	Pathogenic; Nonsense	Kindred 1
			n = 1 Female	-	1FDR; 1SDR
			Kindred 2
			n = 1 Female	-	1FDR
	c.3113G > A	Pathogenic; Nonsense	n = 1 Male	Dx 40 melanoma	1FDR
	c.3113G > A	Pathogenic; Nonsense	n = 1 Female	Dx 52 BCC	1FDR
	c.3209 T > C	VUS	n = 1 Female	Dx 55 breast	2FDR
	c.3362delG	Pathogenic; Frameshift	Kindred 1
			n = 1 Male	-	1SDR
			n = 1 Female	Dx 28 melanoma; Dx 42 breast; Dx 55 SCC/BCC	1FDR
	c.3426_3429del	Pathogenic; Frameshift	n = 1 Female	–	1FDR; 1SDR
PRSS1	c.86A > C	Pathogenic; Missense	n = 1 Male	Dx chronic pancreatitis	Nil PDAC; 1FDR chronic pancreatitis
PRSS1	c.86A > T	Pathogenic; Missense	n = 1 Female	Dx chronic pancreatitis	1FDR; 2SDR
STK11	c.179dup	Pathogenic, Nonsense	n = 1 Male	–	De novo PV
STK11	Exon 2–9 deletion	Pathogenic; Deletion	n = 1 Female	–	De novo PV

FDR first-degree relative; SDR second-degree relative; TDR third-degree relative; CRC colorectal cancer; DCIS ductal carcinoma in situ; BCC basal cell carcinoma; SCC squamous cell carcinoma; RCC renal cell carcinoma. ^a same participant; both VUS identified in affected FDR; ^b same participant; ^c diagnosed PDAC on study

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