rs80359062

chr13-32363367-C-Achr13-32363367-C-Gchr13-32363367-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):c.8165C>A(p.Thr2722Lys) variant causes a missense change involving the alteration of a conserved nucleotide. 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. T2722R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.57

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32363367-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 9340.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.974
• PP5: Variant 13-32363367-C-A is Pathogenic according to our data. Variant chr13-32363367-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 230821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32363367-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8165C>A	p.Thr2722Lys	missense_variant	18/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8165C>A	p.Thr2722Lys	missense_variant	18/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2020

The p.T2722K pathogenic mutation (also known as c.8165C>A), located in coding exon 17 of the BRCA2 gene, results from a C to A substitution at nucleotide position 8165. The threonine at codon 2722 is replaced by lysine, an amino acid with similar properties. Another disease-causing mutation, p.T2722R, has been described in the same codon (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8). This amino acid position is highly conserved in available vertebrate species. This alteration was non-functional in a homology-directed DNA repair (HDR) assay (Ambry internal data). This variant occurs in a structural hotspot region of the protein and is predicted to destabilize the protein and disrupt the native protein-protein (BRCA2-DSS1) interaction (Yang H et al. Science. 2002 Sep;297:1837-48). Based on the majority of available evidence to date, this variant is considered a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.2722 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12145750, 23108138, 18451181, 25146914, 18607349). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRCA2 protein function. This variant has been observed in individual(s) with breast cancer (PMID: 27878467). ClinVar contains an entry for this variant (Variation ID: 230821). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with lysine at codon 2722 of the BRCA2 protein (p.Thr2722Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.76	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.8	N;N
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.87
MutPred		0.90		Gain of methylation at T2722 (P = 0.0203);Gain of methylation at T2722 (P = 0.0203);
MVP		0.96
MPC		0.17
ClinPred		1.0	D
GERP RS		5.5
gMVP		0.89

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: rs80359062; hg19: chr13-32937504;