Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_007294.4(BRCA1):c.1396C>T(p.Arg466Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000929 in 1,613,874 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. R466G) 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 Likely_benign. Variant got -1 ACMG points.
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43094135-G-A is Benign according to our data. Variant chr17-43094135-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37410.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=5}.
Likely benign, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Aug 13, 2021
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Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Apr 19, 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. -
Uncertain significance, criteria provided, single submitter
curation
Sema4, Sema4
May 21, 2021
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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). -
not provided Uncertain:1Benign:1
Likely benign, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
-
The p.Arg466Trp variant was not identified in the literature but was identified in dbSNP (ID: rs80356964) “With other, untested allele”, UMD (1X as an unclassified variant), and the BIC database (4X with unknown clinical importance). It was classified as a benign variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports), increasing the likelihood this variant does not have clinical significance. The p.Arg466 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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 this variant. This variant is classified as predicted benign. -
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
May 02, 2023
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual from a family with suspected hereditary breast and ovarian cancer (Capone et al., 2018); Also known as 1515C>T; This variant is associated with the following publications: (PMID: 15385441, 26272908, 24413733, 12872252, 29061375, 31131967, 15343273, 32377563, 29884841, 31911673) -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Mar 29, 2017
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Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Aug 26, 2021
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BRCA1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Sep 11, 2023
The BRCA1 c.1396C>T variant is predicted to result in the amino acid substitution p.Arg466Trp. This variant was reported in an unknown sample from a validation study of a BRCA1 and BRCA2 NGS-based test (Table S1 in Capone et al 2017. PubMed ID: 29061375). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-41246152-G-A). This variant occurs within a region of the BRCA1 gene that is predicted to be tolerant to variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant has been reported in ClinVar as likely benign and uncertain by outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/37410/). Of note, a different variant impacting the same amino acid (p.Arg466Gly) was documented in a patient with breast cancer (Abulkhair et al. 2018. PubMed ID: 30199306, variant referred to as c.1396C>G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary breast ovarian cancer syndrome Benign:1
Likely benign, criteria provided, single submitter