17-43063936-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):c.5090G>A(p.Cys1697Tyr) 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 Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1697R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4 U:4 O:1
• Conservation: PhyloP100: 4.86

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 Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 16 uncertain 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 ClinVar as [Pathogenic]. Clinvar id is 55392.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906
• PP5: Variant 17-43063936-C-T is Pathogenic according to our data. Variant chr17-43063936-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 37635.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5090G>A	p.Cys1697Tyr	missense_variant	17/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5090G>A	p.Cys1697Tyr	missense_variant	17/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Uncertain:4 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 09, 2011	- -
Likely pathogenic, reviewed by expert panel	curation	ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	Oct 08, 2023	The c.5090G>A variant in BRCA1 is a missense variant predicted to cause substitution of Cysteine by Tyrosine at amino acid 1697 (p.Cys1697Tyr). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). This BRCA1 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.386, above the recommended threshold of 0.28 for prediction of impact on BRCA1 function via protein change. SpliceAI predictor score of 0.02 suggests that the variant has no impact on splicing (score threshold <0.10) (PP3 met). Reported by two calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs: 30209399, PMID: 30765603) (PS3 met). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA1-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PP3, PS3). -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 26, 2023

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5209G>A; This variant is associated with the following publications: (PMID: 18465347, 24729269, 11389159, 15133502, 21447777, 28781887, 17305420, 20516115, 32377563, 32257056, 29884841, 25348405, 24389207, 11157798, 35665744, 30209399, 16528612, 14534301, 30263132, 30765603, 30982232, 29470806) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2023

The p.C1697Y variant (also known as c.5090G>A), located in coding exon 16 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5090. The cysteine at codon 1697 is replaced by tyrosine, an amino acid with highly dissimilar properties. Both this alteration, as well as a close-match at the same codon (p.C1697R), have been reported in multiple HBOC families (Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38:361-8; Biunno I et al. Fam. Cancer. 2014 Sep;13:437-44). In addition, both alterations have demonstrated abnormal protein function with respect to transactivation, protein/peptide binding, protein stability/steady-state levels, and homology-directed repair (Woods NT et al. npg Genomic Medicine. 2016: 1:16001; Vallon-Christersson J et al. Hum. Mol. Genet. 2001 Feb;10:353-60; Glover JN. Fam. Cancer. 2006;5:89-93; Williams RS et al. J. Biol. Chem. 2003 Dec;278:53007-16; Lee MS et al. Cancer Res. 2010 Jun;70:4880-90; Ambry internal data). 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). Internal structural analysis indicates that both amino acid substitutions are predicted to disrupt the protein-protein binding interface of BRCA1 (Clapperton JA et al. Nat. Struct. Mol. Biol. 2004 Jun;11:512-8; Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 1697 of the BRCA1 protein (p.Cys1697Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24729269, 29470806). ClinVar contains an entry for this variant (Variation ID: 37635). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 28781887, 30209399). 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: 11157798, 11389159, 18465347). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 05, 2018

Variant summary: BRCA1 c.5090G>A (p.Cys1697Tyr) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246440 control chromosomes. c.5090G>A has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer. However, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating transcriptional activity, which indicated that the variant abolishes normal transcription (Woods_2016). However, this assay was performed using a partial BRCA1 protein in HEK293 cells, rather than the tissue of interest, which may not accurately reflect clinical significance. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Mar 15, 2013

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 p.Cys1697Tyr variant was not identified in the literature nor was it identified in the Exome Variant Server, HGMD, UMD, COSMIC, LOVD or BIC databases. The p.Cys1697 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Cys1697Tyr variant may impact the protein. In addition, Domchek (2013) notes that this residue is required for BRCA1 carboxyl-terminal (BRCT) domain function in DNA repair and tumor suppression. However, this information is not predictive enough to assume pathogenicity. A different variant at this amino acid position, p.Cys1697Arg (c.5089T>C) has been reported in the literature and in the HGMD, UMD, BIC and LOVD databases. Five functional studies have demonstrated that the p.Cys1697Arg variant has an impact on protein structure or expression (Bergthorsson 2001, Lee 2010, Vallon-Christersson 2001, Williams 2003, Williams 2004) and one study showed segregation of this variant with disease in one family (Vallon-Christersson 2001), which suggests that this residue is important to BRCA1 function. However, it should be noted that these results are limited to the substitution of an amino acid (p.Cys1697Arg) that differs from the variant that was found (p.Cys1697Tyr). In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.6	D;N;.;D;.;.;N;D;D;D;D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D;D;.;D;.;.;D;D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D;D;.;.;D
Polyphen		0.98, 1.0	.;D;.;.;.;D;.;.;.;D;.
Vest4		0.97
MVP		0.99
MPC		0.58
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.88
gMVP		0.92

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: rs397507241; hg19: chr17-41215953;