rs80359195

chr13-32394707-A-Cchr13-32394707-A-Gchr13-32394707-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_000059.4(BRCA2):c.9275A>C(p.Tyr3092Ser) 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. Y3092C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 6.06

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 13 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9275A>C	p.Tyr3092Ser	missense_variant	25/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9275A>C	p.Tyr3092Ser	missense_variant	25/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Dec 07, 2007	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 02, 2023	This missense variant replaces tyrosine with serine at codon 3092 of the BRCA2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study reported the variant protein to have intermediate activity compared to wild-type in a homology-directed DNA repair assay (PMID: 23108138, 29394989). This variant has been reported in an individual affected with breast cancer (PMID: 24916970) and at least one individual with personal or family history of breast and/or ovarian cancer (PMID: 21120943). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Oct 29, 2001	- -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 2023	The p.Y3092S variant (also known as c.9275A>C), located in coding exon 24 of the BRCA2 gene, results from an A to C substitution at nucleotide position 9275. The tyrosine at codon 3092 is replaced by serine, an amino acid with dissimilar properties. In a study utilizing a bioinformatics method that integrates information about protein sequence, conservation, and structure in a protein likelihood ratio, the effect of this alteration was predicted likely deleterious (Karchin R et al. Cancer Inform. 2008;6:203-16). Multiple studies found that this alteration had intermediate activity in a cell-based homology-directed DNA break repair (HDR) functional assay (Hart SN et al. Genet Med, 2019 01;21:71-80; Mesman RLS et al. Genet. Med., 2019 02;21:293-302; Guidugli L et al. Am. J. Hum. Genet., 2018 02;102:233-248; Guidugli L et al. Cancer Res., 2013 Jan;73:265-75). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 16, 2023	This missense variant replaces tyrosine with serine at codon 3092 of the BRCA2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on protein structure and function. Functional studies have reported the variant protein to have intermediate activity relative to wild-type BRCA2 in homology-directed DNA repair assays (PMID: 23108138, 29394989, 29988080), and increased sensitivity to cisplatin and no impact on cell viability in Brca2-deficient mouse embryonic stem cells (PMID: 29988080). This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 26, 2017

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23108138, 24323938, 19043619, 29394989, 29988080, 29884841) -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 29, 2021

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 has been reported to have conflicting or insufficient data to determine the effect on BRCA2 protein function (PMID: 24323938, 23108138, 29394989). This variant has been reported in individuals affected with breast cancer (PMID: 21120943, 24916970), as well as an individual in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52799). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with serine at codon 3092 of the BRCA2 protein (p.Tyr3092Ser). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
Cadd	Uncertain	24
Dann	Benign	0.97
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.76	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.89
MutPred		0.90		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.96
MPC		0.18
ClinPred		0.99	D
GERP RS		5.9
gMVP		0.75

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: rs80359195; hg19: chr13-32968844;