chr17-43063937-A-T

Position:

• chr17-43063937-A-T

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.5089T>A​(p.Cys1697Ser) 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1697R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 5.76

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 strand (size 2) in uniprot entity BRCA1_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr17-43063937-A-G is described in Lovd as [Likely_pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.5089T>A	p.Cys1697Ser	missense_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.5089T>A	p.Cys1697Ser	missense_variant	17/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 09, 2013

The p.C1697S variant (also known as c.5089T>A or 5208T>A) located in coding exon 16 of the BRCA1 gene. This variant results from a T to A substitution at nucleotide position 5089. The cysteine at codon 1697 is replaced by serine, an amino acid with dissimilar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project.To date, this alteration has been detected with an allele frequency of approximately 0.01% (greater than 7800 alleles tested) in our clinical cohort (includes this individual). Based on protein sequence alignment, thisamino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively.Since supporting evidence is limited at this time, the clinical significance ofp.C1697Sremains unclear. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2020

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. This variant disrupts the p.Cys1697 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11389159, 11157798, 18465347, 20516115, 14534301). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. This variant has been reported not to substantially affect BRCA1 protein function (PMID: 30209399). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141077). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with serine at codon 1697 of the BRCA1 protein (p.Cys1697Ser). The cysteine residue is highly conserved and there is a moderate physicochemical difference between cysteine and serine. -

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	0.75
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	.;T;.;.;T;T;.;.;.;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.1	.;M;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-7.5	D;N;.;D;.;.;N;D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0090	D;D;.;D;.;.;D;D;D;D;D
Sift4G	Benign	0.064	T;D;D;D;D;D;D;T;.;.;D
Polyphen		0.76, 1.0	.;P;.;.;.;D;.;.;.;D;.
Vest4		0.94
MVP		0.99
MPC		0.49
ClinPred		0.99	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs80356993; hg19: chr17-41215954;