Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_007294.4(BRCA1):c.4185G>C(p.Gln1395His) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q1395Q) has been classified as Pathogenic.
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 Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 17-43090944-C-G is Pathogenic according to our data. Variant chr17-43090944-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 232793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Hereditary breast ovarian cancer syndrome Pathogenic:2
Oct 31, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: BRCA1 c.4185G>C (p.Gln1395His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. In addition, this variant disrupts the last nucleotide of exon 11, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: three predict the variant abolishes a 5' splicing donor site, and one predicts the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and leads to exon 12 skipping (e.g., Leman_2018). The variant was absent in 242736 control chromosomes (gnomAD). To our knowledge, no occurrence of c.4185G>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. One publication reports experimental evidence evaluating the impact of Q1395H on protein function and found that this missense variant displayed a moderate defect in homologous recombination activity (e.g., Foo_2021). However, the exact nucleotide change utilized for the mutant protein was not disclosed and therefore this study does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 34301763, 29750258, 28993434). Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Sep 09, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 1395 of the BRCA1 protein (p.Gln1395His). This variant also falls at the last nucleotide of exon 11, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 28993434). ClinVar contains an entry for this variant (Variation ID: 232793). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 34301763). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.4185G nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 7493024, 9649133, 12759930, 23239986). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.4185G>C variant (also known as p.Q1395H), located in coding exon 10 of the BRCA1 gene, results from a G to C substitution at nucleotide position 4185. The amino acid change results in glutamine to histidine at codon 1395, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 10, which makes it likely to have some effect on normal mRNA splicing. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). One functional study reported p.Q1395H to confer modestly reduced homologous recombination activity and increased sensitivity to cisplatin and olaparib (Foo TK et al. Cancer Res. 2021 Sep;81(18):4676-4684). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). A different nucleotide substitution at this same position, BRCA1 c.4185G>A (p.Q1395Q) has been shown to cause out-of-frame skipping of coding exon 10 (Claes K et al. Genes Chromosomes Cancer. 2003 Jul;37:314-20; Wappenschmidt B et al. PLoS ONE. 2012 Dec;7:e50800; Gayther SA et al. Nat. Genet.1995 Dec;11:428-33). In addition, as a missense substitution, this variant is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -