Our verdict is Likely benign. Variant got -6 ACMG points: 4P and 10B. PM1PM2BP4_ModerateBP6_Very_Strong
The NM_007294.4(BRCA1):c.997A>G(p.Thr333Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as 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 -6 ACMG points.
PM1
In a region_of_interest Disordered (size 32) in uniprot entity BRCA1_HUMAN there are 17 pathogenic changes around while only 6 benign (74%) in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13811237).
BP6
Variant 17-43094534-T-C is Benign according to our data. Variant chr17-43094534-T-C is described in ClinVar as [Benign]. Clinvar id is 184709.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094534-T-C is described in Lovd as [Benign].
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Published functional studies demonstrate no damaging effect: functionally neutral in three homologous recombination repair complementation assays (Bouwman et al., 2020); Observed in an individual with breast and/or ovarian cancer (Santonocito et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 1116A>G; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24389207, 18680205, 32546644, 32438681, 31131967) -
Oct 30, 2018
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:1
Jun 18, 2019
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance: Benign
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 1 based on posterior probability = 0.000013 -
Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Hereditary cancer-predisposing syndrome Benign:2
Apr 10, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
Feb 17, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This alteration is classified as likely 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. -
Hereditary breast ovarian cancer syndrome Benign:1
Jan 21, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Loss of phosphorylation at T333 (P = 0.0255);Loss of phosphorylation at T333 (P = 0.0255);.;Loss of phosphorylation at T333 (P = 0.0255);.;Loss of phosphorylation at T333 (P = 0.0255);.;.;Loss of phosphorylation at T333 (P = 0.0255);