rs80357209
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM5BP6
The NM_007294.4(BRCA1):c.230C>T(p.Thr77Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,388 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T77SQLV?) has been classified as Pathogenic.
Frequency
Consequence
NM_007294.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.230C>T | p.Thr77Met | missense_variant | 5/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.230C>T | p.Thr77Met | missense_variant | 5/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152080Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251146Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135760
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461308Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 726982
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74294
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:6Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 02, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 10, 2023 | This missense variant replaces threonine with methionine at codon 77 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in a homology-directed repair and a haploid cell proliferation assay (PMID: 30209399, 30219179), and functional studies on ubiquitin-related activities also have reported partial to no impact (PMID: 16403807, 30696104). This variant has been reported in at least one individual each affected with breast, prostate and thyroid cancer (PMID: 22034289, 29684080, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA1_000065). This variant has been identified in 4/251146 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 13, 2023 | - - |
not provided, no classification provided | in vitro | Brotman Baty Institute, University of Washington | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Sep 20, 2012 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2021 | Observed in individuals with breast cancer or thyroid cancer (Fackenthal 2012, Yehia 2018); Published functional studies demonstrate decreased E2 binding and E3 ligase activity, but no impact on BARD1 binding, HDR activity, or cell survival (Morris 2006, Findlay 2018, Starita 2018, Caleca 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (Lek 2016); Also known as 349C>T; This variant is associated with the following publications: (PMID: 22034289, 29684080, 20104584, 24389207, 30219179, 30696104, 30209399, 29106415, 15385441, 20016594, 25823446, 16267036, 27720647, 24489791, 21309043, 26761715, 16403807) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 26, 2023 | The frequency of this variant in the general population, 0.000026 (3/113612 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 22034289 (2012), 16267036 (2005), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)), as well as in an unaffected individual (PMID: 32467295 (2020)). Functional studies have reported this variant had no effect on BARD1 binding (PMID: 30696104 (2019), 35659930 (2022)), BRCA1 splicing (PMID: 26761715 (2016), 21309043 (2011)), or BRCA1 SUMOylation (PMID: 20016594 (2009)). One functional study also reported normal function in haploid cells and little to no change to RNA levels (PMID: 30209399 (2018)). However, one functional study reported reduced ubiquitin ligase activity (PMID: 25823446 (2015), 16403807(2006)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 03, 2023 | Variant summary: BRCA1 c.230C>T (p.Thr77Met) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251146 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.230C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer without strong evidence for pathogenicity (example: Fackenthal_2012; Judkins_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.4484G>T , p.Arg1495Met), providing supporting evidence for a benign role (BIC database). Multiple functional studies (including HDR assay assessement) have reported this variant as functional (example: Findlay_2018 and Clark_2022). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) and benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 21, 2023 | This missense variant replaces threonine with methionine at codon 77 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that this variant does not impact BRCA1 function in a homology-directed repair and a haploid cell proliferation assay (PMID: 30209399, 30219179), and functional studies on ubiquitin-related activities also have reported partial to no impact (PMID: 16403807, 30696104). This variant has been reported in at least one individual each affected with breast, prostate and thyroid cancer (PMID: 22034289, 29684080, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA1_000065). This variant has been identified in 4/251146 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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 | Aug 06, 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. - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 27, 2022 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 13, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at