Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_007294.4(BRCA1):c.3929C>A(p.Thr1310Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,614,078 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely_benign. Variant got -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.1297495).
BP6
Variant 17-43091602-G-T is Benign according to our data. Variant chr17-43091602-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 55053.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=5}.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:1
May 22, 2018
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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May 01, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Jun 20, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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not provided Uncertain:2Benign:1
Feb 03, 2021
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Feb 20, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Observed in individuals with breast or pancreatic cancer, but also in unaffected controls (PMID: 30666157, 33471991, 35980532); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 4048C>A; This variant is associated with the following publications: (PMID: 35980532, 18824701, 15385441, 31131967, 25348012, 33471991, 28717660, 30666157, 15343273, 22737296) -
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). -
Aug 16, 2021
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. -
Apr 20, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces threonine with lysine at codon 1310 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in 4 individuals affected with breast cancer, one individual affected with pancreatic cancer, and one unaffected individual (PMID: 33471991, 30666157; LOVD DB-ID BRCA1_000283; Color internal data). This variant also has been reported in a multifactorial analysis with likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant, and family history of 0.2856, 1.1768 and 6.1835, respectively (PMID: 31131967). This variant has been identified in 20/251182 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 specified Uncertain:1
Aug 14, 2020
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.3929C>A (p.Thr1310Lys) results in a non-conservative amino acid change located in the SC (SQ/TQ cluster) domain that contains several potential ATM phosphorylation sites (PMID: 22193408). Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 394484 control chromosomes, predominantly at a frequency of 0.0011 within the Latino subpopulation (i.e. 51/48248 alleles) in the gnomAD database (v2.1 exomes dataset and v3 genomes dataset), including 1 homozygote. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.1-fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer Syndrome phenotype (0.001), suggesting that the variant could be a benign polymorphism found primarily in populations of Latino origin. To our knowledge, the variant, c.3929C>A, has been reported in the literature in at least two individuals, who were affected with breast- and pancreatic carcinoma (Spearman_2008, Lovecek_2019). These reports however, do 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. Seven other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and six of them classified the variant as VUS, while one called it likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
BRCA1-related cancer predisposition Uncertain:1
Aug 06, 2024
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 threonine with lysine at codon 1310 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). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in 4 individuals affected with breast cancer, one individual affected with pancreatic cancer, and one unaffected individual (PMID: 33471991, 30666157; LOVD DB-ID BRCA1_000283; Color internal data). This variant also has been reported in a multifactorial analysis with likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic variant, and family history of 0.2856, 1.1768 and 6.1835, respectively (PMID: 31131967). This variant has been identified in 20/251182 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. -
Familial cancer of breast Benign:1
Apr 10, 2024
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary cancer Benign:1
Jan 23, 2024
Mendelics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Benign:1
Dec 18, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter