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

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000044498	SCV000072511	benign	Hereditary breast and ovarian cancer syndrome	2020-12-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001353552	SCV000108615	likely benign	not provided	2020-07-29	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18284688, 16905680, 26898890, 27495310, 25479140, 21952622, 25348012, 10923033)
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)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Research and Development, ARUP Laboratories	RCV001642349	SCV001854808	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)	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
Department of Pathology and Laboratory Medicine,Sinai Health System	RCV001353552	SCV000591929	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Val1610Met variant was identified in 6 of 8922 proband chromosomes (frequency: 0.0007) from individuals with hereditary breast and ovarian cancer and prostate cancer (Simard 2007, Caminsky 2016, Jarhelle 2016, Dolman 2013, Kote-Jarai 2011, Lee 2008). The variant was identified in dbSNP (rs80358705) as “with other allele”, in ClinVar (interpreted as "uncertain significance" by Sinai Health System and 3 others, "benign" Invitae and 2 others and "likely benign" by Ambry Genetics and 1 other), LOVD 3.0 (observed 2x) and UMD-LSDB (observed 3x). The variant was identified in control databases in 23 of 245,458 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 23 of 111,150 chromosomes (freq: 0.0002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. In the UMD-LSDB database, the variant co-occurred with a pathogenic BRCA1 variant (p.Arg1443*). Additionally, a clinical laboratory reported the variant occurred with another pathogenic BRCA1 variant (p.Glu1161fsX3). The p.Val1610 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.