Submissions for variant NM_000059.4(BRCA2):c.7601C>T (p.Ala2534Val)

gnomAD frequency: 0.00009  dbSNP: rs74047012

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001085066	SCV000073269	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000590175	SCV000210430	likely benign	not provided	2020-12-18	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25664426, 23415752, 19043619, 21147080, 11240689, 30254663, 30606148, 10815905)
Counsyl	RCV000031691	SCV000220346	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2014-05-22	criteria provided, single submitter	literature only
Ambry Genetics	RCV000220233	SCV000273906	likely benign	Hereditary cancer-predisposing syndrome	2018-10-02	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267807	SCV000695084	likely benign	not specified	2024-02-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7601C>T (p.Ala2534Val) results in a non-conservative amino acid change located in the helical domain (IPR015252) of 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 0.0001 in 250798 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.0001 vs 0.00075), allowing no conclusion about variant significance. c.7601C>T has been reported in the literature in individuals affected with Hereditary Breast and/or Ovarian Cancer without strong evidence for causality (examples: Jimenez_2011, Zuntini_2018, Torrorey-Sawe_2020, Su_2021 and Dorling_2021), as well as unaffected controls (examples: Dong_2021 and Dorling_2021). These reports 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 (i.e. BIC and UMD each report a sample with the common pathogenic variant BRCA1 c.5266dupC (p.Gln1756Profs)), providing supporting evidence for a benign role. One large case-control study did not find this variant as a significant risk allele (Haiman 2013). Two recent reports from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge have reported this variant to be not pathogenic following assessment of its impact on splicing and protein function through various prediction methods, and agreeing to the classification of likely benign assigned by the ENIGMA Consortium (Cline_2019, Padilla_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31294896, 30606148, 32467295, 33471991, 23555315, 21147080, 19043619, 11240689, 26689913, 31112341, 32918181, 23415752, 34917121, 10815905, 32231682, 10644434, 30254663). ClinVar contains an entry for this variant (Variation ID: 38109). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590175	SCV000889135	likely benign	not provided	2023-03-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220233	SCV000911016	benign	Hereditary cancer-predisposing syndrome	2016-02-10	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590175	SCV001148991	uncertain significance	not provided	2019-06-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267807	SCV002551557	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541047	SCV004766907	likely benign	BRCA2-related disorder	2019-10-30	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Sharing Clinical Reports Project (SCRP)	RCV000031691	SCV000054298	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-02-04	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031691	SCV000147139	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	RCV000590175	SCV000592127	likely benign	not provided		no assertion criteria provided	clinical testing	The BRCA2 p.Ala2534Val variant was identified in 3 of 186 proband chromosomes (frequency: 0.0161) from individuals or families with hereditary breast and ovarian cancer (de Juan Jimenez 2010, Stordal 2013). The variant was listed in dbSNP (rs74047012) with a minor allele frequency of 0.001 (1000 Genomes Project), and in the NHLBI Exome Sequencing Project (Exome Variant Server) in 1 of 4406 African American alleles (frequency: 0.0002), although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was also identified in the following databases: ClinVar (6x as likely benign by GeneDx, Counsyl, Ambry Genetics, COGR, Invitae, and SCRP and 1x as uncertain significance by BIC), Clinvitae (4x), Cosmic (found 1x in kidney tumour), LOVD 3.0 (5x), BIC Database (5x, clinical importance unknown, classification pending), and UMD-LSDB (9x as uncertain significance). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.5266dup, p.Gln1756ProfsX74), increasing the likelihood that the p.Ala2534Val variant does not have clinical significance. The variant was classified as “likely benign” by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The variant was not identified in MutDB, ARUP Laboratories, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 25 of 276514 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). It was observed in the African population in 6 of 23976 chromosomes (freq: 0.00025), Latino in 1 of 34394 chromosomes (freq: 0.000029), European (Non-Finnish) in 15 of 126190 chromosomes (freq: 0.000119), and South Asian in 3 of 30740 chromosomes (freq: 0.000098); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Ala2534 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Val impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.
True Health Diagnostics	RCV000220233	SCV000886675	likely benign	Hereditary cancer-predisposing syndrome	2018-09-27	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV002267807	SCV003839274	likely benign	not specified	2022-08-31	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000031691	SCV004243774	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing