Submissions for variant NM_000059.3(BRCA2):c.506A>G (p.Lys169Arg) (rs80358730)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044547	SCV000072560	benign	Hereditary breast and ovarian cancer syndrome	2020-11-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000074532	SCV000108617	likely benign	not specified	2017-11-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000129126	SCV000183844	likely benign	Hereditary cancer-predisposing syndrome	2018-09-06	criteria provided, single submitter	clinical testing	In silico models in agreement (benign);Other data supporting benign classification
Michigan Medical Genetics Laboratories,University of Michigan	RCV000031522	SCV000267730	likely benign	Breast-ovarian cancer, familial 2	2016-04-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000031522	SCV000487798	uncertain significance	Breast-ovarian cancer, familial 2	2015-11-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001281705	SCV000600623	uncertain significance	not provided	2020-03-13	criteria provided, single submitter	clinical testing
Color Health, Inc	RCV000129126	SCV000910662	likely benign	Hereditary cancer-predisposing syndrome	2015-11-16	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000031522	SCV001266518	uncertain significance	Breast-ovarian cancer, familial 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Clinical Services Laboratory,Illumina	RCV001111540	SCV001269104	uncertain significance	Fanconi anemia, complementation group D1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074532	SCV001361906	likely benign	not specified	2019-03-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.506A>G (p.Lys169Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 246020 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (6.1e-05 vs 0.00075), allowing no conclusion about variant significance. c.506A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Davies_2018, Kote-Jarai_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.8537_8538delAG (p.Glu2846Glyfs), BRCA1 c.188T>A (p.Leu63X) in the BIC database), providing supporting evidence for a benign role. A functional study, Houdayer_2012, found the variant to not have an impact on splicing. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant four times as likely benign/benign and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Research and Development, ARUP Laboratories	RCV001642357	SCV001854650	likely benign	Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome	2020-01-20	criteria provided, single submitter	curation
Sharing Clinical Reports Project (SCRP)	RCV000031522	SCV000054127	benign	Breast-ovarian cancer, familial 2	2007-04-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031522	SCV000147027	uncertain significance	Breast-ovarian cancer, familial 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001281705	SCV000591687	uncertain significance	not provided		no assertion criteria provided	clinical testing