ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1974G>C (p.Met658Ile) (rs55678461)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001082658 SCV000075682 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000047669 SCV000167247 benign not specified 2014-02-28 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.
Ambry Genetics RCV000130602 SCV000185477 likely benign Hereditary cancer-predisposing syndrome 2018-12-11 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Counsyl RCV000111744 SCV000488131 uncertain significance Breast-ovarian cancer, familial 1 2016-01-19 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000047669 SCV000593683 uncertain significance not specified 2016-09-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000047669 SCV000698903 likely benign not specified 2021-04-03 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1974G>C (p.Met658Ile) 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 6e-05 in 251078 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (6e-05 vs 0.001), allowing no conclusion about variant significance. c.1974G>C has been reported in the literature in individuals affected with Hereditary Breast and/or Ovarian Cancer (example, Judkins_2005, Lu_2012, Li_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in the BIC database (BRCA1 c.66_67delAG (c.68_69del), p.Glu23fs), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments with a majority consensus leaning towards benign (n=4)/likely benign(n=2) (VUS, n=2). Several submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc RCV000130602 SCV000902675 likely benign Hereditary cancer-predisposing syndrome 2015-06-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590433 SCV001133507 likely benign not provided 2019-06-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590433 SCV001371126 likely benign not provided 2020-04-01 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111744 SCV000144266 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000047669 SCV000591360 benign not specified no assertion criteria provided clinical testing The p.Met658Ile variant has been previously identified in the BIC (n=27 as unknown clinical importance), LOVD (n=1) and Exome Server (n=3 out of 13001 chromosomes) databases and appears to be a low frequency variant. This variant is listed in the dbSNP database (ID#:rs55678461) but no frequency information was provided, and so the prevalence of this variant in the general population is not known. It was reported once in the literature in an in silico study where conservation and biophysical properties of the variant were analyzed and used for classification. The variant was predicted to be neutral (Abkevich_2004_15235020). This residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. However, our lab has previously identified this variant in one individual who also had a second pathogenic variant and increasing the likelihood this variant is benign. Myriad genetics has reported this variant as a polymorphism in Jan 2010. In summary, based on the above information this variant is classified as a benign variant.

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