17-43057093-G-C

Position:

• chr17-43057093-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_007294.4(BRCA1):​c.5236C>G​(p.His1746Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 O:1
• Conservation: PhyloP100: 5.96

Genes affected

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89
• PP5: Variant 17-43057093-G-C is Pathogenic according to our data. Variant chr17-43057093-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 531399.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, not_provided=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5236C>G	p.His1746Asp	missense_variant	19/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5236C>G	p.His1746Asp	missense_variant	19/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 1746 of the BRCA1 protein (p.His1746Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 25036526). ClinVar contains an entry for this variant (Variation ID: 531399). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 11877378, 30209399, 30765603). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Nov 14, 2023	PS3, PM2_sup, PP3. According to the ClinGen ENIGMA BRCA1 v1.0.0 criteria we chose these criteria: PS3 (strong pathogenic): PS3_strong:Table 9: Reported by two calibrated studies to affect protein function similar to pathogenic control variants (PMIDs:30209399, Findlay, 30765603, Fernandes), PM2 (supporting pathogenic): Absent from gnomAD PM2_supp, PP3 (supporting pathogenic): BayesDel noAF score 0.3731 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2024

The p.H1746D variant (also known as c.5236C>G), located in coding exon 18 of the BRCA1 gene, results from a C to G substitution at nucleotide position 5236. The histidine at codon 1746 is replaced by aspartic acid, an amino acid with similar properties. This variant has been reported in an individual diagnosed with ovarian cancer and in a cohort of Chinese individuals who underwent multi-gene panel testing for HBOC risk assessment (Gleicher N et al. PLoS One, 2014 Jul;9:e102370; Shao D et al. Cancer Sci, 2020 Feb;111:647-657). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). A transcriptional activation assay found that this variant had <80% activity relative to wildtype and was, thus, considered deleterious (Fernandes VC et al. J Biol Chem, 2019 04;294:5980-5992). This variant was also reported as non-functional in a homology directed repair assay, but functional in an assay of cisplatin resistance (Adamovich AI et al. Am J Hum Genet. 2022 Apr;109(4):618-630). Based on internal structural analysis, this variant is anticipated to result in a decrease in structural stability (Ambry internal data; Wu Q et al. Mol Cell, 2016 Feb;61:434-448). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Oct 21, 2022

It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with ovarian cancer (PMID: 25036526 (2014)). Functional studies are supportive of a damaging effect on protein function (PMIDs: 30765603 (2019), 30209399 (2018), 11877378 (2002)), however additional studies are needed to determine the global effect of this variant on BRCA1 protein function. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

BRCA1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 18, 2024

The BRCA1 c.5236C>G variant is predicted to result in the amino acid substitution p.His1746Asp. This variant has been reported in individuals with a history of ovarian cancer (Table 3, Gleicher et al. 2014. PubMed ID: 25036526), and was reported as uncertain with a high level of evidence in a cohort of Chinese individuals who underwent testing for high risk hereditary breast and ovarian cancer risk assessment (Table S2, Shao et al. 2019. PubMed ID: 31742824). Functional studies indicate this variant reduces BRCA1-BACH1 binding (Joo et al. 2002. PubMed ID: 11877378). Additional functional studies demonstrated that this variant had an intermediate effect on protein function (Supplemental Table 1, Findlay et al. 2018. PubMed ID: 30209399), and another study showed that this variant demonstrated markedly reduced reporter transcription activation function relative to wild type in vitro and was considered deleterious (Table S2, Fernandes et al. 2019. PubMed ID: 30765603). To our knowledge, this variant has not been reported in a large population database, indicating this variant is rare. This variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from uncertain to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/531399/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Breast-ovarian cancer, familial, susceptibility to, 1 Other:1

not provided, no classification provided

in vitro

Brotman Baty Institute, University of Washington

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	.;T;.;.;T;T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	2.0	.;M;.;.;.;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-7.1	D;N;.;D;.;.;N;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.023	D;D;.;D;.;.;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		0.54, 1.0	.;P;.;.;.;D;.;.
Vest4		0.88
MVP		0.89
MPC		0.22
ClinPred		0.98	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.86
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80357146; hg19: chr17-41209110;