ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6131G>T (p.Gly2044Val) (rs56191579)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001086174 SCV000072867 benign Hereditary breast and ovarian cancer syndrome 2020-11-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130525 SCV000185394 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
Counsyl RCV000031602 SCV000220301 likely benign Breast-ovarian cancer, familial 2 2014-05-10 criteria provided, single submitter literature only
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000413633 SCV000492497 uncertain significance Breast neoplasm criteria provided, single submitter research
GeneDx RCV000044854 SCV000512376 likely benign not provided 2020-10-27 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26332594, 15168169, 29192238, 17100994, 21218378, 19016756, 16949048, 24884479, 12624724, 25802882, 18779604, 26315209, 27383479, 27124784, 28111427, 23555315, 24843434, 30415210, 29802286, 31131967, 32486089)
Genetic Services Laboratory, University of Chicago RCV000421588 SCV000593750 likely benign not specified 2016-12-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130525 SCV000683756 likely benign Hereditary cancer-predisposing syndrome 2015-04-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000044854 SCV001133853 likely benign not provided 2019-07-16 criteria provided, single submitter clinical testing
Mendelics RCV000031602 SCV001139137 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000031602 SCV001270228 benign 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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV001112564 SCV001270229 benign 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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000421588 SCV001361750 benign not specified 2019-06-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6131G>T (p.Gly2044Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251324 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (4.4e-05 vs 0.00075), allowing no conclusion about variant significance. The variant, c.6131G>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, predominantly Japanese and Korean ethnicities, along with the variant co-occurring with different pathogenic variants (Silva_2015; Ohmoto_2018; BIC database; internal database), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Sharing Clinical Reports Project (SCRP) RCV000031602 SCV000054209 benign Breast-ovarian cancer, familial 2 2011-03-02 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031602 SCV000146776 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358172 SCV001553843 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Gly2044Val variant was identified in 15 of 5097 proband chromosomes (frequency: 0.003) from Korean, Japanese, Brazilian and Hawaiian individuals or families with with breast or ovarian cancer or a family history of breast and ovarian cancers, and was present in 1 of 724 control chromosomes from healthy individuals (Carney 2010, Han S-H 2006, Hirotsu 2014, Jalkh 2012, Kawahara 2004 , Kim 2006, Silva 2014, Sugano 2008). The variant was found to cooccur with a pathogenic BRCA1 variant (c.3759G>T p.E1214X) in 1 affected Brazilian proband (Silva 2014). The variant was also identified in dbSNP (ID: rs56191579) “With other allele”, ClinVar (with conflicting interpretations of pathogenicity; submitters: benign by Ambry Genetics and Sharing Clinical Reports Project (SCRP); likely benign by Counsyl, GeneDx, Invitae and Genetic Services Laboratory (University of Chicago); uncertain significance by BIC and Laboratory of Genomics and Molecular Biology (A.C.Camargo Cancer Center)), Clinvitae (5x), BIC Database (10x with clinical importance unknown, classification pending), and in control databases in 10 of 245748 chromosomes at a frequency of 0.00004 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: European Non-Finnish in 1 of 111442 chromosomes (frequency: 0.000009) and East Asian in 9 of 17242 chromosomes (frequency: 0.0005). The variant was not identified in Genesight-COGR, Cosmic, LOVD 3.0, ARUP Laboratories, and Zhejiang Colon Cancer Database. The p.Gly2044 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 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, HumanSpliceFinder) 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.

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