Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001082658 | SCV000075682 | benign | Hereditary breast ovarian cancer syndrome | 2024-01-28 | criteria provided, single submitter | clinical testing | |
Gene |
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 | This alteration is classified as likely 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 | RCV000111744 | SCV000488131 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2016-01-19 | criteria provided, single submitter | clinical testing | |
Genetic Services Laboratory, |
RCV000047669 | SCV000593683 | uncertain significance | not specified | 2016-09-28 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000047669 | SCV000698903 | likely benign | not specified | 2023-03-06 | 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. Nine 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=1)/likely benign(n=5) (VUS, n=3). 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 Diagnostics, |
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 | 2022-08-19 | criteria provided, single submitter | clinical testing | |
Ce |
RCV000590433 | SCV001371126 | likely benign | not provided | 2021-03-01 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000130602 | SCV002538074 | likely benign | Hereditary cancer-predisposing syndrome | 2021-07-15 | criteria provided, single submitter | curation | |
Center for Genomic Medicine, |
RCV000047669 | SCV002551024 | likely benign | not specified | 2024-07-31 | criteria provided, single submitter | clinical testing | |
University of Washington Department of Laboratory Medicine, |
RCV000130602 | SCV003849593 | 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). |
Prevention |
RCV004554654 | SCV004719067 | likely benign | BRCA1-related disorder | 2020-09-22 | criteria provided, single submitter | clinical testing | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). |
Breast Cancer Information Core |
RCV000111744 | SCV000144266 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 1 | 2002-05-29 | no assertion criteria provided | clinical testing | |
Department of Pathology and Laboratory Medicine, |
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. |