rs80359072

chr13-32363456-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000059.4(BRCA2):c.8254A>T(p.Ile2752Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I2752V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 0.546

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 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 13 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8254A>T	p.Ile2752Phe	missense_variant	18/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8254A>T	p.Ile2752Phe	missense_variant	18/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 05, 2023	This missense variant replaces isoleucine with phenylalanine at codon 2752 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 2/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000302) and in suspected hereditary breast and ovarian cancer families (PMID: 21232165, 22366370). A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 0.3348, respectively (PMID: 31131967). 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 05, 2022	This missense variant replaces isoleucine with phenylalanine at codon 2752 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 2/60463 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000302) and in suspected hereditary breast and ovarian cancer families (PMID: 21232165, 22366370). A multifactorial analysis has reported co-occurrence and family history likelihood ratios for pathogenicity of 1.0498 and 0.3348, respectively (PMID: 31131967). 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, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 10, 2023	The p.I2752F variant (also known as c.8254A>T), located in coding exon 17 of the BRCA2 gene, results from an A to T substitution at nucleotide position 8254. The isoleucine at codon 2752 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in Slovenian and Croatian breast and/or ovarian cancer families (Stegel V et al. BMC Med Genet. 2011 Jan 14;12:9; Levanat S et al. Gene. 2012 May 1;498(2):169-76). This amino acid position is not well 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 01, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 2752 of the BRCA2 protein (p.Ile2752Phe). 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: 21232165, 22366370). ClinVar contains an entry for this variant (Variation ID: 52538). 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 with a negative predictive value of 95%. 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 22, 2021

This variant is associated with the following publications: (PMID: 31131967, 22366370, 19043619, 21232165) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Benign	15
Dann	Benign	0.95
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.65	D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Benign	-0.33	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Vest4		0.57
MutPred		0.59		Loss of methylation at K2750 (P = 0.0856);Loss of methylation at K2750 (P = 0.0856);
MVP		0.93
MPC		0.17
ClinPred		0.91	D
GERP RS		-1.1
gMVP		0.65

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: rs80359072; hg19: chr13-32937593; COSMIC: COSV66456764; COSMIC: COSV66456764;