rs80358909

Positions:

• chr13-32344563-C-A
• chr13-32344563-C-G
• chr13-32344563-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000059.4(BRCA2):​c.6847C>A​(p.Pro2283Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000146 in 1,367,144 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 4.11

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6847C>A	p.Pro2283Thr	missense_variant	12/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6847C>A	p.Pro2283Thr	missense_variant	12/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1367144 Hom.: 0 Cov.: 26 AF XY: 0.00000292 AC XY: 2 AN XY: 684592

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000194

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Jun 10, 2024	According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PM2 (supporting pathogenic): Absent from controls , BP1 (strong benign): outside a (potentially) clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1). -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 23, 2023	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2283 of the BRCA2 protein (p.Pro2283Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 23683081). ClinVar contains an entry for this variant (Variation ID: 462417). 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 not expected to disrupt BRCA2 protein function. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Nov 30, 2022

It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 33471991 (2021) , 31853058 (2020), 23683081 (2013)), as well as in healthy individuals (PMID: 33471991 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2024

The p.P2283T variant (also known as c.6847C>A), located in coding exon 11 of the BRCA2 gene, results from a C to A substitution at nucleotide position 6847. The proline at codon 2283 is replaced by threonine, an amino acid with highly similar properties. This alteration was observed in 1 of 256 families from northern Spain with breast and/or ovarian cancer; but the variant did not segregate with disease in the family, which had two case of ovarian cancer (Blay P et al. BMC Cancer 2013; 13:243). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	21
DANN	Uncertain	0.98
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.18	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Uncertain	0.24	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N;N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0060	D;D
Vest4		0.40
MutPred		0.47		Loss of disorder (P = 0.0812);Loss of disorder (P = 0.0812);
MVP		0.94
MPC		0.14
ClinPred		0.91	D
GERP RS		4.1
gMVP		0.34

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: rs80358909; hg19: chr13-32918700;