Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_ModerateBP6_Very_Strong
The NM_007294.4(BRCA1):c.3724A>G(p.Thr1242Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1242S) has been classified as Likely 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]
Computational evidence support a benign effect (MetaRNN=0.17748773).
BP6
Variant 17-43091807-T-C is Benign according to our data. Variant chr17-43091807-T-C is described in ClinVar as [Benign]. Clinvar id is 54982.Status of the report is reviewed_by_expert_panel, 3 stars.
Uncertain significance, criteria provided, single submitter
clinical testing
Ambry Genetics
Aug 03, 2023
The p.T1242A variant (also known as c.3724A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3724. The threonine at codon 1242 is replaced by alanine, an amino acid with similar properties. This alteration has been detected in 1/2575 unselected patients with breast cancer and 0/2809 healthy control individuals from a Malaysian cohort (Wen WX et al. J. Med. Genet. 2018 02;55:97-103). This alteration was classified as benign in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence, tumor pathology, and case-control data (Parsons MT. et al. Hum Mutat. 2019 09;40(9):1557-1578). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jul 14, 2016
- -
Uncertain significance, criteria provided, single submitter
curation
Sema4, Sema4
Dec 05, 2021
- -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Nov 25, 2004
- -
Benign, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Jun 18, 2019
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 = 0.000025 -
not provided Benign:1
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Dec 02, 2019
Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28993434, 16267036, 31131967) -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter