Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_007294.4(BRCA1):c.1895G>A(p.Ser632Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,794 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 Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20323801).
BP6
Variant 17-43093636-C-T is Benign according to our data. Variant chr17-43093636-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54385.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=7}.
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:1
Dec 30, 1999
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
Feb 02, 2024
BRCAlab, Lund University
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
Jul 22, 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 serine with asparagine at codon 632 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 reported in 2 individuals affected with breast or ovarian cancer (PMID: 32438681) and in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000173). This variant has been identified in 1/251112 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. -
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). -
May 08, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.S632N variant (also known as c.1895G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 1895. The serine at codon 632 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Santonocito C et al. Cancers (Basel), 2020 May;12:; Boga I et al. Eur J Breast Health, 2023 Jul;19:235-252). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
Sep 08, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces serine with asparagine at codon 632 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 reported in 2 individuals affected with breast or ovarian cancer (PMID: 32438681) and in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000173). This variant has been identified in 1/251112 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:2
Sep 16, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The BRCA1 c.1895G>A; p.Ser632Asn variant (rs80356983, ClinVar Variation ID: 54385) is reported in the literature in two individuals affected with breast or ovarian cancer (Santonocito 2020) and in individuals included in a breast cancer or family history of breast cancer cohort (Boga 2023). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.428). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Boga I et al. A Multicenter Study of Genotype Variation/Demographic Patterns in 2475 Individuals Including 1444 Cases With Breast Cancer in Turkey. Eur J Breast Health. 2023 Jul 3;19(3):235-252. PMID: 37415649. Santonocito C et al. Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. Cancers (Basel). 2020 May 19;12(5):1286. PMID: 32438681. -
Feb 26, 2024
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; Observed in individual(s) with breast and/or ovarian cancer (PMID: 32438681); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 2014G>A; This variant is associated with the following publications: (PMID: 12531920, 15235020, 16518693, 23704879, 10923033, 15343273, 32438681) -
not specified Uncertain:1
Mar 06, 2024
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.1895G>A (p.Ser632Asn) results in a conservative amino acid change in the encoded protein sequence. Three 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 251112 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1895G>A has been reported in the literature in individuals affected with Hereditary Breast And/or Ovarian Cancerwithout strong evidence for causality (examples: Tram_2013, Santonocito_2020, Bucalo_2023, Boga_2023). 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 in BIC database (BRCA1 c.2071del, p.Arg691fs), providing supporting evidence for a benign role. One publication has reported this variant is located in a region where missense variants are unlikely to be pathogenic (Dines_2020). The following publications have been ascertained in the context of this evaluation (PMID: 37415649, 35165121, 32438681, 23704879, 31911673). ClinVar contains an entry for this variant (Variation ID: 54385). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
BRCA1-related disorder Uncertain:1
Nov 11, 2022
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The BRCA1 c.1895G>A variant is predicted to result in the amino acid substitution p.Ser632Asn. This variant has been reported in two individuals with breast and/or ovarian cancer (Table 2, Santonocito et al. 2020. PubMed ID: 32438681). It has also been reported as clinically significant in an in silico variant interpretation study (Table S3, Tram et al 2013. PubMed ID: 23704879). This variant is reported in 1 of ~251,000 of alleles in gnomAD (http://gnomad.broadinstitute.org/variant/17-41245653-C-T) and has conflicting interpretations of benign and uncertain significance https://preview.ncbi.nlm.nih.gov/clinvar/variation/54385/). 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
May 31, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Loss of phosphorylation at S632 (P = 0.0499);Loss of phosphorylation at S632 (P = 0.0499);.;Loss of phosphorylation at S632 (P = 0.0499);.;Loss of phosphorylation at S632 (P = 0.0499);.;