rs80357078
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM5PP3_ModerateBP6
The NM_007294.4(BRCA1):c.5365G>T(p.Ala1789Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000103 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1789G) has been classified as Uncertain significance.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.5365G>T | p.Ala1789Ser | missense_variant | 21/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.5365G>T | p.Ala1789Ser | missense_variant | 21/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461880Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727238
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3Benign:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 09, 2017 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | Dec 23, 2003 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 07, 2023 | This missense variant replaces alanine with serine at codon 1789 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in transcription activation, homology-directed DNA repair, a haploid cell proliferation and structural stability assays (PMID: 20516115, 29884841, 30209399) and exhibits a moderate decrease in phosphopeptide binding and specificity assays (PMID: 20516115). This variant has been reported in an individual affected with early onset breast cancer with no family history (PMID: 15887246). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.5365G>A (p.Ala1789Thr), has been identified in individuals affected by breast and/or ovarian cancer (PMID: 18680205, 20737206, 30264118, 30287823, Color internal data) and has been reported to impair BRCA1 protein function in several functional studies (PMID: 18680205, 19493677, 20737206, 28781887, 29884841, 30209399, 32546644), suggesting that Ala at this position is important for the protein function. However, the same functional assays, that reported the p.Ala1789Thr variant to be defected, found our variant in question, p.Ala1789Ser, has no impact on BRCA1 function (PMID: 29884841, 30209399). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not specified Benign:3
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 01, 2023 | This missense variant replaces alanine with serine at codon 1789 of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported that this variant does no impact BRCA1 function in protein stability, phosphopeptide binding and specificity, transcription activation and homology-directed repair assays (PMID: 20516115, 28781887, 30257991) and in a haploid cell proliferation assay (PMID: 30209399) This variant has been reported in an individual affected with early-onset breast cancer with no family history of disease (PMID: 15887246). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.5365G>A (p.Ala1789Thr), has been identified in individuals affected by breast and/or ovarian cancer (PMID: 18680205, 20737206, 30264118, 30287823, Color internal data) and has been reported to impair BRCA1 protein function in several functional studies (PMID: 18680205, 19493677, 20737206, 28781887, 29884841, 30209399, 32546644), suggesting that Ala at this position is important for the protein function. However, the same functional assays, that reported the p.Ala1789Thr variant to be defected, found our variant in question, p.Ala1789Ser, has no impact on BRCA1 function (PMID: 29884841, 30209399). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 27, 2021 | 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Clinvar: LB (VKGL data-share consensus), VUS (Counsyl, Color, BIC - 1 individual). Not in gnomad. Reported in one individual with breast cancer at age 37 (Bonadona 2005). Functional and in silico assays classify variant as not pathogenic (Findlay 2018, Woods 2016, Lee 2010). One in silico study calls variant deleterious as a Serine at this position disrupts the BRCT superfamily conserved G[G/A] motif (Karchin 2008). - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 08, 2023 | This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1789 of the BRCA1 protein (p.Ala1789Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 15887246). ClinVar contains an entry for this variant (Variation ID: 55553). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 20516115, 30257991, 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at