Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP3
The NM_007294.4(BRCA1):āc.5071A>Gā(p.Thr1691Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,456,898 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. T1691P) has been classified as Uncertain significance.
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 17 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43067610-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.835
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Other:1
Uncertain significance, criteria provided, single submitter
clinical testing
Baylor Genetics
Jan 26, 2024
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Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Mar 23, 2017
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not provided, no classification provided
in vitro
Brotman Baty Institute, University of Washington
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not provided Uncertain:2
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Feb 04, 2016
This variant is denoted BRCA1 c.5071A>G at the cDNA level, p.Thr1691Ala (T1691A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant, also known as BRCA1 5190A>G using alternate nomenclature, was reported to be associated with RNA similar to wild type in a study of splicing defects using stimulated lymphocytes (Houdayer 2012). BRCA1 Thr1691Ala was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Thr1691Ala occurs at a position that is conserved in mammals and is located within the BRCT1 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Thr1691Ala is pathogenic or benign. We consider it to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jul 12, 2016
Variant summary: The BRCA1 c.5071A>G (p.Thr1691Ala) variant involves the alteration of a conserved nucleotide located in BRCT domain. p.Thr1691Ala was predicted to destabilize the BRCT domain and could have a functional impact (Caputo_2012). 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 3/5 splice prediction tools predict no significant impact on normal splicing, which was confirmed by RNA analysis in patient's T lymphoctes (Houdayer_2012). This variant is absent in 121146 control chromosomes. This variant has been reported in patients in literature or databases without convincing evidence supporting pathogenicity of this variant. Taken together, this variant is classified as VUS until more information is available. -
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Nov 03, 2022
This missense variant replaces threonine with alanine at codon 1691 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 homology-directed repair, subcellular localization and phosphopeptide binding assays (PMID: 30257991) and the variant retains intermediate activity in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in an individual affected with ovarian cancer (PMID 24504028). This variant has not been identified 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
Mar 31, 2020
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. -
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
MGZ Medical Genetics Center
Feb 09, 2024
ACMG codes applied following ENIGMA VCEP rules: PM2_SUP -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Apr 01, 2023
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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 function (PMID: 30209399, 30257991, 32546644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 55371). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24504028, 34597585). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1691 of the BRCA1 protein (p.Thr1691Ala). -