Submissions for variant NM_000059.4(BRCA2):c.4928T>C (p.Val1643Ala)

dbSNP: rs28897731

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044524	SCV000072537	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000416148	SCV000210531	likely benign	not provided	2019-06-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27062684, 18951461, 24916970, 21203900, 26207792, 18824701, 18279628, 27741520, 21702907, 25348012, 27527004, 30606148, 32806537)
Ambry Genetics	RCV000163029	SCV000213517	likely benign	Hereditary cancer-predisposing syndrome	2019-01-24	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	RCV000077341	SCV000267773	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000416148	SCV000493200	likely benign	not provided	2022-04-01	criteria provided, single submitter	clinical testing	BRCA2: BP1, BP4
Color Diagnostics, LLC DBA Color Health	RCV000163029	SCV000910874	benign	Hereditary cancer-predisposing syndrome	2016-05-24	criteria provided, single submitter	clinical testing
Mendelics	RCV000077341	SCV001139097	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000416148	SCV001469436	uncertain significance	not provided	2020-11-20	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000416148	SCV002010361	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307380	SCV002600390	likely benign	not specified	2023-12-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4928T>C (p.Val1643Ala) results in a non-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 3.9e-05 in 1600364 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00075), allowing no conclusion about variant significance. c.4928T>C has been reported in the literature in individuals affected with breast or ovarian cancer without strong evidence of causality (e.g. Konecny_2011, Lu_2012, Peixoto_2014, Spearman_2008, Fanale_2021, Dorling_2021), and was also found in controls (Dorling_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.5263_5264insC, p.Ser1755?fs and BRCA2 c.9976A>T, p.Lys3326Ter in the BIC database), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (Biswas_2020). These results showed no damaging effect of this variant in a well-established mouse embryonic stem cell based 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. The following publications have been ascertained in the context of this evaluation (PMID: 33293522, 21702907, 21203900, 22476429, 24916970, 18824701, 33471991, 31131967, 34178674). 12 other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and reported the variant with conflicting assessments and a majority consensus as likely benign/benign (n=9) (VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000163029	SCV003852214	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000077341	SCV004845749	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000044524	SCV005374664	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-08	criteria provided, single submitter	curation	According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose this criterion: BP1 (strong benign): BP1_Strong for silent substitution, missense or in-frame insertion, deletion or delins variants outside a (potentially) clinically important functional domain AND no splicing predicted (spliceAI:BRCA2:0.0)
Sharing Clinical Reports Project (SCRP)	RCV000077341	SCV000109138	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077341	SCV000146507	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	RCV000044524	SCV000586956	uncertain significance	Hereditary breast ovarian cancer syndrome	2016-04-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353540	SCV000591932	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Val1643Ala variant was identified in 1 of 698 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer and was found not to segregate with disease in the proband’s two family members with breast cancer (Fernandes 2016). The variant was also identified in dbSNP (ID: rs28897731) as "With other allele", ClinVar (classified as benign by SCRP; as likely benign by GeneDx, Ambry Genetics, Invitae, and Michigan Medical Genetics; and as uncertain significance by Humangenetik Teubingen, COGR, and BIC), and LOVD 3.0 (classified as uncertain or NA by 3 submitters). The variant has been identified by our laboratory in at least three individuals with breast cancer; one of whom also has a co-occurring pathogenic ATM variant (c.5712dup, p.Ser1905Ilefs*25). The variant was identified in control databases in 7 of 239572 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 1 of 32346 chromosomes (freq: 0.00003), European in 3 of 109484 chromosomes (freq: 0.00003), and South Asian in 3 of 28946 chromosomes (freq: 0.0001); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Val1643 residue is not conserved in mammals and 5 of 5 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.