Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7
The NM_007294.4(BRCA1):āc.2497T>Cā(p.Leu833=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,792 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 Likely benign (ā ā ).
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]
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.88).
BP6
Variant 17-43093034-A-G is Benign according to our data. Variant chr17-43093034-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 415591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.443 with no splicing effect.
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Aug 21, 2019
- -
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Dec 19, 2017
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Genetics and Molecular Pathology, SA Pathology
Apr 22, 2020
BRCA1:c.2497T>C is a single nucleotide variant in exon 11 (of 24) that encodes a synonymous (silent) substitution in which Leucine is retained at position 833, NP_009225.1(BRCA1):p.(Leu833=) (BP7). This variant has not been published in the scientific literature in association with BRCA1 disorders.The nucleotide position of BRCA1:c.2497T>C is not conserved (PhyloP=-0.44) and is outside any known BRCA1 functional domain. This variant is not predicted to impact splicing (SpliceAI=0.00) (BP4). The variant (rs887578121) is recorded in population databases (2 heterozygous (1 heterozygous in non-cancer dataset), 0 homozygous / 152160 alleles, highest frequency 0.0024% (African/African American) (gnomAD 3.1.2)) (PM2_Supporting). BRCA1:c.2497T>C is recorded in ClinVar (Variation ID: 415591) as likely benign by multiple clinical laboratories (without conflict). It has not been reported in HGMD. -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Sep 15, 2019
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
Likely benign, criteria provided, single submitter