Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.5282T>C(p.Phe1761Ser) 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 Likely 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 domain BRCT 2 (size 99) in uniprot entity BRCA1_HUMAN there are 69 pathogenic changes around while only 15 benign (82%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.962
PP5
Variant 17-43051113-A-G is Pathogenic according to our data. Variant chr17-43051113-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Hereditary breast ovarian cancer syndrome Pathogenic:3
Aug 22, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.5282T>C (p.Phe1761Ser) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251176 control chromosomes. c.5282T>C has been reported in the literature in at-least one individual affected with Hereditary Breast Cancer (Sugano_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a greater than 99% probability of pathogenicity based on a transcriptional activation (TA) assay (Woods_2016). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Oct 12, 2023
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: curation
PS3, PM2_supporting, PP3. According to the ACMG standard criteria we chose these criteria: PS3 (strong pathogenic): Findlay et al., 2018: LOF; Fernandes et al., 2019: fclass 5; Lee et al., 2010: strong functional effect, PM2 (supporting pathogenic): absent from controls, PP3 (supporting pathogenic): REVEL: 0.872 ; PRIOR: 0.66 -
Jun 22, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 19016756). ClinVar contains an entry for this variant (Variation ID: 55505). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 10811118, 20516115, 28781887, 30209399, 30765603). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1761 of the BRCA1 protein (p.Phe1761Ser). -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2Other:1
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.F1761S variant (also known as c.5282T>C), located in coding exon 19 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5282. The phenylalanine at codon 1761 is replaced by serine, an amino acid with highly dissimilar properties. This alteration was detected in one individual from a cohort of 135 Japanese patients suspected of having HBOC (Sugano K et al. Cancer Sci. 2008 Oct;99:1967-76). This alteration was also severely compromised in multiple functional assays including in binding activity, transcription activation and binding specificity (Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Hayes F et al. Cancer Res. 2000 May;60:2411-8). Internal structural analysis identified this alteration as being within a mutational hotspot within the BRCT2 domain and predicts that this substitution is likely to disturb the local structure in a manner that is comparable to other nearby pathogenic alterations (Ambry internal data; Varma AK et al. Biochemistry. 2005 Aug;44:10941-6). 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. -
Aug 29, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This missense variant replaces phenylalanine with serine at codon 1761 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). This variant has been reported to impact BRCA1 function in a homology-directed repair assay, haploid human cell proliferation assay and yeast transcription activation assays (PMID: 10811118, 20516115, 29884841, 30209399). This variant has been reported in three individuals affected with breast cancer and/or ovarian (PMID: 19016756, 34072659; Color internal data) and a multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.067 and 6.917, respectively (PMID: 31131967). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -