Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6
The NM_007294.4(BRCA1):c.3211G>A(p.Glu1071Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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 Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.29726332).
BP6
Variant 17-43092320-C-T is Benign according to our data. Variant chr17-43092320-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184828.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=4}.
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces glutamic acid with lysine at codon 1071 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002509; UMD database; Color internal data). A multifactorial analysis has reported this variant with posterior probability of being pathogenic of 0.004486 based in part to likelihood ratios of pathogenicity for co-occurrence and health history of one family of 1.0331 and 0.2137, respectively (PMID: 31131967). This variant has been identified in 1/250450 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. -
Aug 19, 2020
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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. -
Mar 23, 2023
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
not specified Uncertain:1
Jun 27, 2022
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.3211G>A (p.Glu1071Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250450 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3211G>A has been reported in a large study, evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), in 1/60466 cases, and 0/53461 controls (Dorling_2021 through LOVD). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A multifactorial likelihood analysis predicted this variant to be Likely Benign (Parsons_2019). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1
Apr 03, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces glutamic acid with lysine at codon 1071 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_002509; UMD database; Color internal data). A multifactorial analysis has reported this variant with posterior probability of being pathogenic of 0.004486 based in part to likelihood ratios of pathogenicity for co-occurrence and health history of one family of 1.0331 and 0.2137, respectively (PMID: 31131967). This variant has been identified in 1/250450 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. -
not provided Uncertain:1
Apr 29, 2022
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at a significant frequency in large population cohorts (gnomAD); Observed in an individual with developmental disorders undergoing exome sequencing (Turner et al., 2019); Also known as 3330G>A; This variant is associated with the following publications: (PMID: 25348012, 31785789, 15343273, 31131967) -
BRCA1-related disorder Uncertain:1
Dec 27, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
The BRCA1 c.3211G>A variant is predicted to result in the amino acid substitution p.Glu1071Lys. This variant has been reported in an individual with breast cancer (Table S14, Breast Cancer Association Consortium et al. 2021. PubMed ID: 33471991). This variant occurs within a region of the BRCA1 gene that is predicted to be tolerant to missense variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant is reported in 0.00089% of alleles in individuals of European (non-Finnish) descent in gnomAD. This variant has been reported in ClinVar as uncertain and likely benign by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/184828/). Although we suspect that this variant could be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary breast ovarian cancer syndrome Benign:1
Nov 04, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter