chr17-43063951-T-A

Position:

• chr17-43063951-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_007294.4(BRCA1):​c.5075A>T​(p.Asp1692Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. D1692H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense, splice_region
• Scores: Splicing: ADA: 0.7225
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:6 O:1
• Conservation: PhyloP100: 4.92

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a domain BRCT 1 (size 94) in uniprot entity BRCA1_HUMAN there are 74 pathogenic changes around while only 17 benign (81%) in NM_007294.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43067608-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.865

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5075A>T	p.Asp1692Val	missense_variant, splice_region_variant	17/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.5075A>T	p.Asp1692Val	missense_variant, splice_region_variant	17/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 16, 2023	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 05, 2011	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2015	This variant is denoted BRCA1 c.5075A>T at the cDNA level and p.Asp1692Val (D1692V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). This variant, also known as BRCA1 5194A>T using alternate nomenclature, has been reported in one individual with ovarian cancer (Akbari 2011). BRCA1 Asp1692Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Asp1692Val occurs at a position that is conserved in mammals and is located in the BRCT domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Despite some evidence suggesting pathogenicity, we consider BRCA1 Asp1692Val to be a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 03, 2024	The BRCA1 c.5075A>T (p.Asp1692Val) variant has been reported in the published literature in an individual with ovarian cancer (PMID: 21965345 (2011)), and characterized as being non-functional in a saturation genome editing assays measuring DNA repair-dependent cell proliferation (PMIDs: 30209399 (2018)). At this codon, a different variant (c.5075A>C (p.Asp1692Ala)) has been shown to cause nearly abolished BRCA1 transactivation activity (PMIDs: 30458859 (2018), 27495310 (2017)), while other amino acid substitutions (e.g. p.Asp1692His, p.Asp1692Tyr, p.Asp1692Asn) result in partial to near normal levels of BRCT domain stability, binding activity and specificity (PMID: 20516115 (2010)). The c.5075A>T (p.Asp1692Val) variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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 deleterious or benign. Additional analysis using software algorithms for the prediction of the effect of nucleotide changes on BRCA1 mRNA splicing yielded inconclusive findings. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2023

The p.D1692V variant (also known as c.5075A>T) is located in coding exon 16 of the BRCA1 gene. The aspartic acid at codon 1692 is replaced by valine, an amino acid with highly dissimilar properties. This variant was identified in one out of 1345 ovarian cancer patients (Akbari MR et al. J. Med. Genet. 2011 Nov; 48(11):783-6). 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by protein in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

research

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Jan 31, 2014

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 1692 of the BRCA1 protein (p.Asp1692Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 21965345). ClinVar contains an entry for this variant (Variation ID: 55383). 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: 30209399). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;.;.;T;T;.;.;.;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;T;D;D;D;D;D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.86	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.51	D
MutationAssessor	Uncertain	2.8	.;M;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.8	D;N;.;D;.;.;N;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;D;.;D;.;.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;.;.;D
Polyphen		0.011, 1.0	.;B;.;.;.;D;.;.;.;D;.
Vest4		0.83
MVP		0.96
MPC		0.19
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.87
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.72
dbscSNV1_RF	Benign	0.54
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.32		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs397509222; hg19: chr17-41215968;