Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM2BP4_StrongBP6_Very_StrongBP7
The NM_007294.4(BRCA1):c.1863T>C(p.His621=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar 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]
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
Variant 17-43093668-A-G is Benign according to our data. Variant chr17-43093668-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 184433.Status of the report is reviewed_by_expert_panel, 3 stars.
BP7
Synonymous conserved (PhyloP=1.2 with no splicing effect.
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Mar 11, 2016
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 and/or ovarian cancer Benign:1
Likely benign, no assertion criteria provided
clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Dec 13, 2012
- -
Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1
Likely benign, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Jun 29, 2017
Synonymous substitution variant, with low bioinformatic likelihood to result in a splicing aberration (Splicing prior probability 0.02; http://priors.hci.utah.edu/PRIORS/). -
not provided Benign:1
Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Jun 01, 2022
BRCA1: PM2:Supporting, BP4, BP7 -
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
-
The p.His621His variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. It was not identified in the literature, nor the UMD, LOVD or BIC databases. The prevalence of this variant in the general population is not known. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for it. This variant meets our laboratory's classification criteria as predicted benign. -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Sep 06, 2017
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