Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5207T>G(p.Val1736Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.888
PP5
Variant 17-43057122-A-C is Pathogenic according to our data. Variant chr17-43057122-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Review Status: criteria provided, single submitter
Collection Method: curation
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Jul 20, 2021
Color Diagnostics, LLC DBA Color Health
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces valine with glycine at codon 1736 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 shown that this variant impacts BRCA1 function in transcription activation and in a haploid cell proliferation assay (PMID: 20516115, 30209399). A different missense variant p.Val1738Ala is reported as disease-causing in ClinVar (variation ID 37648), suggesting that valine or similar amino acid at this position may be important for function. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Nov 27, 2019
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.V1736G pathogenic mutation (also known as c.5207T>G), located in coding exon 18 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5207. The valine at codon 1736 is replaced by glycine, an amino acid with dissimilar properties. A transcription activation assay found that this variant had <80% activity relative to wildtype and was, thus, considered deleterious (Fernandes VC et al. J. Biol. Chem., 2019 04;294:5980-5992). Additionally, a functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222) and another functional study found this alteration to be severely defective in all assays (Lee MS et al. Cancer Res., 2010 Jun;70:4880-90). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Other:1
Feb 20, 2004
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro
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Hereditary breast ovarian cancer syndrome Pathogenic:1
Apr 11, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.5207T>G (p.Val1736Gly) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 277208 control chromosomes. c.5207T>G has been reported in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, internal data). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A functional study demonstrated the variant to decrease protein stability, phosphopeptide binding activity, phosphopeptide binding specificity and transcriptional activity of BRCA1 (Lee_2010). Multiple studies involving computational analysis predict this variant to be pathogenic/deleterious (Cao_2019, Thompson_2016, Woods_2016, Karchin_2007, Pavlicek_2004). Different variants at the same codon such as c.5207delT, c.5207T>C are listed in databases (ClinVar, HGMD) with disease causing outcome indicating the variant to be located in a mutational hotspot and the clinical relevance of the Val1736 residue. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -