Submissions for variant NM_000059.4(BRCA2):c.506A>G (p.Lys169Arg)

gnomAD frequency: 0.00008  dbSNP: rs80358730

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044547	SCV000072560	benign	Hereditary breast ovarian cancer syndrome	2024-01-27	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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000031522	SCV000267730	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000031522	SCV000487798	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2015-11-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001281705	SCV000600623	uncertain significance	not provided	2021-05-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129126	SCV000910662	likely benign	Hereditary cancer-predisposing syndrome	2015-11-16	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000031522	SCV001266518	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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 Laboratory Services, 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	benign	not specified	2021-10-23	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 5.6e-05 in 251168 control chromosomes, predominantly at a frequency of 0.00011 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 Syndrome (5.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.506A>G has been reported in the literature in as a VUS in settings of somatic and germline multigene panel testing in individuals with a wide variety of cancers, example, male prostate cancer, breast cancer, the cancer genome atlas (TGCA) cohort, ALL, low-grade serous carcinomas (LGSCs) (example, Kote-Jarai_2011, Davies_2018, Lu_2015, Zhang_2015, Zhang_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the BIC database (BRCA2 c.8537_8538delAG, p.Glu2846Glyfs; BRCA1 c.188T>A, p.Leu63X) and with a driver KRAS mutation, p.G12V in an individual with low-grade serous carcinomas (LGSCs) (Zhang_2021), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (example, Biswas_2020). These results showed no damaging effect of this variant in a mouse embryonic stem cell-based functional assay examining the ability to rescue the lethality of Brca2 null mESC as well as sensitivity to six DNA damaging agents including ionizing radiation and a PARP inhibitor. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments and a predominant consensus towards a benign/likely benign (n=6) outcome (VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798044	SCV002043114	likely benign	Breast and/or ovarian cancer	2023-01-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129126	SCV002533921	likely benign	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001281705	SCV003799533	likely benign	not provided	2022-05-02	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031522	SCV000054127	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2007-04-03	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031522	SCV000147027	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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
BRCAlab, Lund University	RCV000031522	SCV004243837	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541040	SCV004762218	uncertain significance	BRCA2-related disorder	2024-01-19	no assertion criteria provided	clinical testing	The BRCA2 c.506A>G variant is predicted to result in the amino acid substitution p.Lys169Arg. This variant has been documented in the literature as a variant of uncertain significance in individuals undergoing a wide variety of cancer testing, but no additional data supports its pathogenicity (Kote-Jarai et al. 2011. PubMed ID: 21952622; Hondow et al. 2011. PubMed ID: 21702907). In silico splicing algorithms predict this variant will create a cryptic splice junction; however functional analysis of splicing indicated it does not alter splicing (Alamut Visual Plus v.1.6.1; Table S3b, Houdayer et al. 2012. PubMed ID: 22505045; Table S1, Wai et al. 2020. PubMed ID: 32123317). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/37941/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.