Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5324T>A(p.Met1775Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M1775R) has been classified as Pathogenic.
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 Pathogenic. Variant got 16 ACMG points.
PM1
In a strand (size 2) in uniprot entity BRCA1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43051071-A-C is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.899
PP5
Variant 17-43051071-A-T is Pathogenic according to our data. Variant chr17-43051071-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 17695.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43051071-A-T is described in Lovd as [Pathogenic]. Variant chr17-43051071-A-T is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5Other:1
Jun 02, 2021
Genetics and Molecular Pathology, SA Pathology
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The BRCA1 c.5324T>A variant is classified as Pathogenic (PS3, PM2, PM5, PP3, PP5) -
Aug 10, 2015
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Pathogenic
Review Status: reviewed by expert panel
Collection Method: curation
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 -
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance: Pathogenic
Review Status: criteria provided, single submitter
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces methionine with lysine at codon 1775 in the BRCT2 domain of the BRCA1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein is highly defective for specific phosphopeptide recognition and transcriptional activity (PMID: 18285836, 20516115). This variant has also been reported to cause loss of BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been observed in two individuals affected with familial breast cancer (PMID: 18285836) and reported to be disease-causing based on multifactorial likelihood analyses (PMID: 18285836, 21990134). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Met1775Arg, is a well documented pathogenic mutation (Clinvar variation ID: 17694), indicating that methionine at this position is important for BRCA1 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic. -
Feb 24, 2020
Ambry Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.M1775K variant (also known as c.5324T>A), located in coding exon 19 of the BRCA1 gene, results from a T to A substitution at nucleotide position 5324. The methionine at codon 1775 is replaced by lysine, an amino acid with similar properties. This alteration, as well as a known pathogenic close match alteration BRCA2 p.M1775R, were non-functional in many different assays including a colony size assay, a haploid cell survival assay, multiple transcription activation assays, and multiple protein binding and specificity assays (Thouvenot P et al. PLoS Genet. 2016 06;12:e1006096; Findlay GM et al. Nature. 2018 10;562:217-222; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32; Drikos I et al. Proteins. 2009 Nov;77:464-76). This alteration was identified in two families in the literature and segregated with disease in both. In one family, this variant was found in cis with BRCA2 p.D1778N, a likely pathogenic splicing alteration (Tischkowitz M et al. Eur. J. Hum. Genet. 2008 Jul;16:820-32). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research
- -
Nov 13, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1775 of the BRCA1 protein (p.Met1775Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 18285836). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17695). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 18285836, 20516115, 30209399). This variant disrupts the p.Met1775 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 793963, 7545954, 12400015, 19493677, 20516115, 22144684). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -