ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.6131G>C (p.Gly2044Ala) (rs56191579)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001085159 SCV000072866 benign Hereditary breast and ovarian cancer syndrome 2020-11-14 criteria provided, single submitter clinical testing
Ambry Genetics RCV000166682 SCV000217490 benign Hereditary cancer-predisposing syndrome 2015-08-15 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.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768600 SCV000324853 uncertain significance Breast and/or ovarian cancer 2015-12-11 criteria provided, single submitter clinical testing
GeneDx RCV000431388 SCV000512377 likely benign not specified 2017-08-17 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000431388 SCV000600680 uncertain significance not specified 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166682 SCV000683755 likely benign Hereditary cancer-predisposing syndrome 2017-05-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000431388 SCV000694942 likely benign not specified 2019-06-17 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6131G>C (p.Gly2044Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251134 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6131G>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer (Diez_2003, Martinez-Ferrandis_2003, Palomba_2009, Jalkh_2012). Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.5984dup, p.Asn1995LysfsX8; BRCA2 c.6208C>T, p.Q1994X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant four times as likely benign/benign and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586884 SCV000887865 uncertain significance not provided 2017-07-12 criteria provided, single submitter clinical testing
Baylor Genetics RCV001330945 SCV001522805 uncertain significance Fanconi anemia, complementation group D1 2020-05-05 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sharing Clinical Reports Project (SCRP) RCV000031601 SCV000054208 benign Breast-ovarian cancer, familial 2 2010-04-22 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031601 SCV000146775 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353819 SCV000592031 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Gly2044Ala variant was identified in 5 of 2336 proband chromosomes (frequency: 0.003) from Spanish, Lebanese and Sardinian (Italian) individuals or families with sporadic breast cancer, early onset breast cancer and/or HBOC and was not identified in 606 control chromosomes from healthy individuals (Palomba 2009 , Martinez-Ferrandis 2003, Jalkh 2012, Diez 2003). In 1 proband, the variant was found to co-occur with a truncating BRCA2 mutation (p.Q1994X) and hence determined to be a rare polymorphism because it altered a non-conservative residue and was absent in controls (Martinez-Ferrandis 2003). The variant was also identified in dbSNP (ID: rs56191579) “With other allele”, ClinVar (with conflicting interpretations of pathogenicity: classified benign by Ambry Genetics and SCRP (Sharing Clinical Reports Project); likely benign by GeneDx and Invitae; and uncertain significance by CHEO Genetics Diagnostic Lab, Quest Diagnostics Nichols Institute San Juan Capistrano and BIC), Clinvitae (4X), UMD-LSDB (3x as 3-UV), and BIC Database (3x clinical importance unknown, classification pending). The variant was not identified in COGR, Cosmic, ARUP Laboratories, and Zhejiang Colon Cancer Databases. The variant was also identified by our laboratory in 1 individual with breast cancer and in control databases in 6 of 245748 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 15274 chromosomes (freq: 0.00007), Other in 1 of 5472 chromosomes (freq: 0.0002), Latino in 1 of 33566 chromosomes (freq: 0.00003), European Non-Finnish in 3 of 111442 chromosomes (freq: 0.00003), and not in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Gly2044 residue is not conserved in mammals and 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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