Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_007294.4(BRCA1):āc.3362A>Gā(p.Asn1121Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. N1121D) has been classified as Likely benign.
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=0.09063476).
BP6
Variant 17-43092169-T-C is Benign according to our data. Variant chr17-43092169-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37527.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=7}.
Likely benign, criteria provided, single submitter
curation
University of Washington Department of Laboratory Medicine, University of Washington
Mar 23, 2023
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter
curation
Sema4, Sema4
Nov 19, 2021
- -
Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Feb 05, 2015
This alteration is classified as 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. -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Benign:1
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Nov 25, 2004
- -
Benign, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Feb 24, 2012
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Sep 26, 2016
- -
not provided Uncertain:2Benign:1
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Dec 03, 2019
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 26306726, 31131967) -
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
May 12, 2023
In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 26306726 (2015)). A multifactorial analysis study has reported that this variant is likely not pathogenic (PMID: 31131967 (2019)). The frequency of this variant in the general population, 0.000016 (4/250354 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Jul 29, 2020
The BRCA1 c.3362A>G; p.Asn1121Ser variant (rs80356919) is reported in the literature in an individual affected with ovarian cancer, but without a clear disease association (Minucci 2015). This variant is reported in ClinVar (Variation ID: 37527), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The asparagine at codon 1121 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Additionally, a multifactorial likelihood analysis categorized this variant as likely benign (Parsons 2019). However, given the lack of clinical and functional data, the significance of the p.Asn1121Ser variant is uncertain at this time. References: Minucci A et al. Clinical impact on ovarian cancer patients of massive parallel sequencing for BRCA mutation detection: the experience at Gemelli hospital and a literature review. Expert Rev Mol Diagn. 2015;15(10):1383-1403. Parsons MT et al. Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification. Hum Mutat. 2019;40(9):1557-1578. -
Hereditary breast ovarian cancer syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter
clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Sep 26, 2023
- -
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Oct 27, 2023
- -
Uncertain significance, criteria provided, single submitter
clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State
Nov 16, 2021
- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Oct 03, 2019
Variant summary: BRCA1 c.3362A>G (p.Asn1121Ser) 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 1.6e-05 in 250354 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3362A>G has been reported in the literature at-least once in an individual affected with sporadic and/or familial Ovarian Cancer (Minucci_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; benign/likely benign, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance. -