Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_007294.4(BRCA1):c.106T>A(p.Ser36Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,458 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S36A) 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]
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 17 uncertain in NM_007294.4
PM2
Very rare variant in population databases, with high coverage;
Uncertain significance, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Sep 19, 2023
This missense variant replaces serine with threonine at codon 36 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has shown that the variant protein is functional in a human haploid cell line-based survival assay (PMID: 30209399). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Feb 23, 2023
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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Jan 14, 2022
The BRCA1 c.106T>A; p.Ser36Thr variant (rs905812561), to our knowledge, is not reported in the medical literature associated with disease but is reported in ClinVar (Variation ID: 489704). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The serine at codon 36 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.605). One in vitro functional study demonstrates no significant effect on homology-directed repair activity (Starita 2015). However, given the lack of clinical and functional data, the significance of the p.Ser36Thr variant is uncertain at this time. References: Starita LM et al. Massively Parallel Functional Analysis of BRCA1 RING Domain Variants. Genetics. 2015 Jun;200(2):413-22. PMID: 25823446. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Aug 16, 2022
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 not expected to disrupt BRCA1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 25823446, 30209399). ClinVar contains an entry for this variant (Variation ID: 489704). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 36 of the BRCA1 protein (p.Ser36Thr). -
Breast-ovarian cancer, familial, susceptibility to, 1 Other:1
Loss of ubiquitination at K32 (P = 0.1601);Loss of ubiquitination at K32 (P = 0.1601);Loss of ubiquitination at K32 (P = 0.1601);Loss of ubiquitination at K32 (P = 0.1601);Loss of ubiquitination at K32 (P = 0.1601);Loss of ubiquitination at K32 (P = 0.1601);Loss of ubiquitination at K32 (P = 0.1601);Loss of ubiquitination at K32 (P = 0.1601);Loss of ubiquitination at K32 (P = 0.1601);Loss of ubiquitination at K32 (P = 0.1601);Loss of ubiquitination at K32 (P = 0.1601);Loss of ubiquitination at K32 (P = 0.1601);Loss of ubiquitination at K32 (P = 0.1601);