Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3PM1PM2PM5PP3_ModeratePP5_Very_Strong
The NM_007294.4(BRCA1):c.5053A>G(p.Thr1685Ala) 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 (★★★). ClinVar reports functional evidence for this variant: "SCV000076762: Experimental studies have shown that this missense change affects BRCA1 function (PMID:20516115, 27272900).; SCV005395176: At least one functional study reports experimental evidence evaluating an impact on protein function and showed a damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). PMID:30209399, 38439815, 29446198; SCV005373669: Experimental studies have shown that this missense change affects BRCA1 function (Findlay et al., 2018; Thouvenot et al., 2016; Lee et al., 2010).; SCV000213512: Multiple functional studies have found this variant to be non-functional including a phosphopeptide binding assay; a binding specificity assay; a protease sensitivity assay; a homology-directed DNA repair assay, and a haploid cell survival assay (Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69; Findlay GM et al. Nature, 2018 10;562:217-222).; SCV004360135: Multiple functional studies have reported the mutant protein to be non-functional in a phosphopeptide binding assay, a homology-directed DNA repair assay, and cell growth/survival assay (PMID:20516115, 27272900, 30209399, 30257991).; SCV000210194: Published functional studies demonstrate a damaging effect with respect to: stability, binding activity and specificity, transcription activity, and protease sensitivity (Lee 2010, Thouvenot 2016, Woods 2016, Findlay 2018, Fernandes 2019);". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1685S) 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]
BRCA1 Gene-Disease associations (from GenCC):
BRCA1-related cancer predisposition
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
Our verdict: Pathogenic. The variant received 20 ACMG points.
PS3
PS3 evidence extracted from ClinVar submissions: SCV000076762: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 27272900).; SCV005395176: At least one functional study reports experimental evidence evaluating an impact on protein function and showed a damaging effect of this variant on homology directed repair (HDR) activity (e.g. Findlay_2018). PMID: 30209399, 38439815, 29446198; SCV005373669: Experimental studies have shown that this missense change affects BRCA1 function (Findlay et al., 2018; Thouvenot et al., 2016; Lee et al., 2010).; SCV000213512: Multiple functional studies have found this variant to be non-functional including a phosphopeptide binding assay; a binding specificity assay; a protease sensitivity assay; a homology-directed DNA repair assay, and a haploid cell survival assay (Lee MS et al. Cancer Res. 2010 Jun;70(12):4880-90; Petitalot A et al. Mol Cancer Res, 2019 01;17:54-69; Findlay GM et al. Nature, 2018 10;562:217-222).; SCV004360135: Multiple functional studies have reported the mutant protein to be non-functional in a phosphopeptide binding assay, a homology-directed DNA repair assay, and cell growth/survival assay (PMID: 20516115, 27272900, 30209399, 30257991).; SCV000210194: Published functional studies demonstrate a damaging effect with respect to: stability, binding activity and specificity, transcription activity, and protease sensitivity (Lee 2010, Thouvenot 2016, Woods 2016, Findlay 2018, Fernandes 2019);
PM1
In a hotspot region, there are 22 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 11 benign, 78 uncertain 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 chr17-43067628-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55365.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.868
PP5
Variant 17-43067629-T-C is Pathogenic according to our data. Variant chr17-43067629-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 55364.Status of the report is reviewed_by_expert_panel, 3 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.