Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_007294.4(BRCA1):c.1924G>C(p.Asp642His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D642G) 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]
Variant 17-43093607-C-G is Benign according to our data. Variant chr17-43093607-C-G is described in ClinVar as [Benign]. Clinvar id is 54401.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093607-C-G is described in Lovd as [Benign].
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Apr 30, 2021
Variant summary: BRCA1 c.1924G>C (p.Asp642His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251006 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1924G>C has been reported in the literature as a VUS in individuals undergoing clinical genetic testing for breast cancer (example Judkins_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Subsequently, studies utilizing multifactorial probability models have reported this variant with a neutral outcome based on a low posterior probability of pathogenicity (example, Lindor_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as likely benign. Based on peer consensus and the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Jul 07, 2015
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Sep 10, 2020
DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.1924G>C, in exon 10 that results in an amino acid change, p.Asp642His. This sequence change does not appear to have been previously described in patients with BRCA1-related disorders. This sequence change was absent in the gnomAD database (dbSNP rs80357344). The p.Asp642His change affects a moderately conserved amino acid residue located in the DNA binding domain of the BRCA1 protein. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asp642His substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Asp642His change remains unknown at this time. -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:2
Benign, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Aug 10, 2015
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000014 -
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
May 29, 2002
- -
Likely benign, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Aug 15, 2023
- -
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Feb 19, 2022
- -
Benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 18, 2014
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. -
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Dec 18, 2017
- -
not provided Benign:2
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Jul 06, 2017
- -
Likely benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Nov 03, 2018
- -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter