Submissions for variant NM_000059.4(BRCA2):c.6131G>T (p.Gly2044Val)

gnomAD frequency: 0.00001  dbSNP: rs56191579

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001086174	SCV000072867	benign	Hereditary breast ovarian cancer syndrome	2024-01-18	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: 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.
Counsyl	RCV000031602	SCV000220301	likely benign	Breast-ovarian cancer, familial, susceptibility to, 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 Diagnostics, LLC DBA Color Health	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, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000031602	SCV001270228	benign	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). 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 Laboratory Services, 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130525	SCV003850963	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).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492315	SCV004240335	likely benign	Breast and/or ovarian cancer	2022-07-18	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000031602	SCV000054209	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-02	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031602	SCV000146776	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	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.