Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong
The NM_007294.4(BRCA1):c.946A>G(p.Ser316Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000372 in 1,614,080 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S316N) 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]
Variant 17-43094585-T-C is Benign according to our data. Variant chr17-43094585-T-C is described in ClinVar as [Benign]. Clinvar id is 37709.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094585-T-C is described in Lovd as [Benign].
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3Benign:2
Benign, no assertion criteria provided
clinical testing
Sharing Clinical Reports Project (SCRP)
Mar 18, 2009
- -
Uncertain significance, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Jan 12, 2018
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
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 = 2.21E-06 -
Uncertain significance, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
May 29, 2002
- -
Uncertain significance, criteria provided, single submitter
Uncertain significance, criteria provided, single submitter
curation
Sema4, Sema4
Dec 07, 2021
- -
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 05, 2018
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. -
not provided Benign:3
Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Apr 25, 2021
This variant is associated with the following publications: (PMID: 23893897, 16518693, 12531920, 16267036, 15385441, 18273839, 26689913, 26246475, 18284688, 22144684, 25925381, 28477318, 26913838, 27062684, 25479140, 24094589, 33087888) -
Likely benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Oct 13, 2022
- -
Benign, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Oct 28, 2021
- -
not specified Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Sep 17, 2018
Variant summary: BRCA1 c.946A>G (p.Ser316Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 277152 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (4.7e-05 vs 0.001), allowing no conclusion about variant significance. The variant, c.946A>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Lee_2008, Azzollini_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported in the UMD database (BRCA1 c.3228_3229delAG, p.Gly1077ALafsX8; BRCA2 c.6209_6212delAAAG, p.Glu2070ValfsX10), providing supporting evidence for a benign role. Multiple functional studies showed no impact on splicing, no sensitivity increase to ionizing radiation and an HDR assay showed no significant changes from wild-type (Anczukow_2008, Cochran_2015, Lu_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS x3, likely benign x2, benign x1). Based on the evidence outlined above, the variant was classified as likely benign. -
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter
clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
May 23, 2023
- -
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.Ser316Gly variant was identified at least once in a large cohort of 55630 individuals referred for BRCA1 mutation testing (Judkins 2005). The variant was also identified in dbSNP (ID: rs55874646) “With non-pathogenic allele”, LOVD, the BIC database (6X with unknown clinical importance), and in UMD (5X as a unclassified variant). In UMD the variant was listed twice as co-occurring with a pathogenic mutation in either BRCA1 or BRCA2 (BRCA1 c.3228 3229delAG (p.Gly1077AlafsX8) and BRCA2 c.6209 6212delAAAG (p.Glu2070ValfsX10)), increasing the likelihood that this variant does not have clinical significance. In addition, one in silico study suggests that the variant does not confer a high oncogenic risk (Burk-Herrick 2005). The variant was listed in the NHLBI Exome Sequencing Project with a frequency of 0.0002 in European American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. The p.Ser316 residue is conserved in mammals; however, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and 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. -
Hereditary breast ovarian cancer syndrome Benign:1