Submissions for variant NM_000059.3(BRCA2):c.4828G>A (p.Val1610Met) (rs80358705)

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044498	SCV000072511	benign	Hereditary breast and ovarian cancer syndrome	2019-12-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000074530	SCV000108615	likely benign	not specified	2018-02-21	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	RCV000130783	SCV000185676	likely benign	Hereditary cancer-predisposing syndrome	2018-10-31	criteria provided, single submitter	clinical testing	Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV000074530	SCV000591929	uncertain significance	not specified	2014-01-22	criteria provided, single submitter	clinical testing
Integrated Genetics/Laboratory Corporation of America	RCV000074530	SCV000694805	benign	not specified	2020-11-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4828G>A (p.Val1610Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 250074 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (9.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.4828G>A has been reported in the literature in individuals affected with Breast and Ovarian Cancer (example, Lee_2008, Kote-Jarai_2011, Simard_2007, Caminsky_2016, Jarhelle_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least two known co-occurrences with other pathogenic variant(s) have been reported (UMD database-BRCA1 c.4327C>T, p.Arg1443*; BIC database-BRCA1 c.3481_3491delGAAGATACTAG, p.Glu1161_Ser1164?fs), providing supporting evidence for a benign role. Two recent reports from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge have classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four have classified the variant as Benign/Likely Benign and two classified the variant as uncertain significance citing overlapping references utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as benign.
Color Health, Inc	RCV000130783	SCV000910745	benign	Hereditary cancer-predisposing syndrome	2017-01-25	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV001112023	SCV001269637	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.
Illumina Clinical Services Laboratory,Illumina	RCV000031508	SCV001269638	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.
Sharing Clinical Reports Project (SCRP)	RCV000031508	SCV000054113	benign	Breast-ovarian cancer, familial 2	2009-08-31	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031508	SCV000146488	uncertain significance	Breast-ovarian cancer, familial 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Medical Genetics, University Hospital of North Norway	RCV000031508	SCV000301448	uncertain significance	Breast-ovarian cancer, familial 2	2016-05-01	no assertion criteria provided	clinical testing