ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3814A>G (p.Met1272Val) (rs80358624)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203673 SCV000072284 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130732 SCV000185623 likely benign Hereditary cancer-predisposing syndrome 2018-03-20 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV001703944 SCV000210596 likely benign not provided 2018-12-19 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17100994, 28263838, 21520273, 14973102, 20104584, 16949048, 24817641, 30287823, 31825140)
Counsyl RCV000083100 SCV000489068 uncertain significance Breast-ovarian cancer, familial 2 2016-08-12 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044271 SCV000694720 uncertain significance not specified 2019-06-25 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3814A>G (p.Met1272Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-06 in 226788 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3814A>G has been reported in the literature in individuals affected with Breast Cancer (Suter_2004, Kim_2006, Han_2006, Borg_2010, Zanella_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. 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) cites the variant as uncertain significance twice, likely benign three times and once as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Health, Inc RCV000130732 SCV000910980 benign Hereditary cancer-predisposing syndrome 2017-05-02 criteria provided, single submitter clinical testing
Mendelics RCV000083100 SCV001139073 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083100 SCV000115174 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083100 SCV000146302 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 RCV001353829 SCV000591876 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Met1272Val variant was identified in 4 of 7082 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast cancer and was not identified in 653 control chromosomes from healthy individuals (Borg 2010, Capanu 2011, Han 2006, Suter 2004). The variant was also identified in dbSNP (ID: rs80358624) “With other allele”; in the Exome Variant Server project in 1 of 8585 European American alleles; the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 1 of 56282 chromosomes (frequency: 0.00001777) from a population of European (Non-Finnish) individuals, and 1 of 10174 chromosomes from a Latino population, 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 found in HGMD (1X as “unknown”), the BIC database (3X with unknown clinical importance), UMD (2X as an unknown variant) and the ClinVar database 4 times with conflicting classifications (1X as benign from the sharing clinical reports project, 1X as likely benign by GeneDx and 2X as uncertain significance (Ambry and BIC)). The p.Met1272 residue is not conserved in mammals and the variant amino acid Valine (Val) is present in rat and chickens increasing the likelihood that this variant does not have clinical significance. In addition, 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. Of note, 4 out of 5 in-silico splicing software predict the creation of a 3' splice site, but the effect of this variant on splicing cannot be determined without further evaluation. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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