Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4BP6
The NM_007294.4(BRCA1):c.2222C>T(p.Ser741Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,694 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S741C) 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 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-43093309-GA-GTTTCTAGTTTCTCTTCTTTTTCTTCTCTTGGAAGGCTAGGATTGACAAATTCTTT is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.3346821).
BP6
Variant 17-43093309-G-A is Benign according to our data. Variant chr17-43093309-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54507.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=4}.
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Mar 17, 2023
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 2341C>T; This variant is associated with the following publications: (PMID: 25782689, 15001988, 12531920, 16518693, 27616075, 30212499, 15829246, 16905680, 16267036, 15343273, 35370679, 33471991) -
Uncertain significance, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Jun 01, 2023
In the published literature, this variant has been reported in individuals with breast/ovarian cancer (PMIDs: 27616075 (2016), 16905680 (2007), 16267036 (2005)). In one of the individuals with breast cancer, this variant co-occurred with a pathogenic variant in the BRCA1 gene, suggesting it was not the primary cause of disease (PMID: 16267036 (2005)). The frequency of this variant in the general population, 0.000008 (2/251070 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Feb 01, 2023
- -
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter
curation
University of Washington Department of Laboratory Medicine, University of Washington
Mar 23, 2023
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Jul 31, 2018
- -
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
May 21, 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. -
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Feb 20, 2004
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Counsyl
Jan 16, 2018
- -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter