ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4643C>T (p.Thr1548Met)

gnomAD frequency: 0.00001  dbSNP: rs273900737
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203649 SCV000076629 uncertain significance Hereditary breast ovarian cancer syndrome 2023-11-24 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1548 of the BRCA1 protein (p.Thr1548Met). This variant is present in population databases (rs273900737, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 55249). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 28781887, 30765603). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000130001 SCV000184826 likely benign Hereditary cancer-predisposing syndrome 2018-06-13 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
GeneDx RCV000505759 SCV000210181 uncertain significance not provided 2016-02-01 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4643C>T at the cDNA level, p.Thr1548Met (T1548M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). Using alternate nomenclature this variant would be defined as BRCA1 4762C>T. BRCA1 Thr1548Met has not, to our knowledge, been published in the literature as pathogenic or benign. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Thr1548Met occurs at a position that is not conserved and is located in a region of interaction with multiple proteins (Cantor 2001, Yarden 1999). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on the currently available information, we consider BRCA1 Thr1548Met to be a variant of uncertain significance.
Counsyl RCV000112371 SCV000488310 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2016-02-19 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000130001 SCV000904984 likely benign Hereditary cancer-predisposing syndrome 2016-01-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001269177 SCV001448461 uncertain significance not specified 2022-10-31 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4643C>T (p.Thr1548Met) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251282 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4643C>T has not been reported in the literature in individuals affected with Breast or Ovarian Cancer outside of references to the BIC database (e.g. Woods_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant on transcriptional activity (Woods_2016, Fernandes_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three laboratories classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112371 SCV000145137 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2010-09-18 no assertion criteria provided clinical testing

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