rs431825368

Positions:

• chr13-32376751-A-G
• chr13-32376751-A-T

Variant summary

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

The NM_000059.4(BRCA2):​c.8714A>G​(p.Tyr2905Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000889 in 1,461,872 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: 0.0000089 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 4.72

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8714A>G	p.Tyr2905Cys	missense_variant	21/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8714A>G	p.Tyr2905Cys	missense_variant	21/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8345A>G	p.Tyr2782Cys	missense_variant	21/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*772A>G		non_coding_transcript_exon_variant	20/26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*772A>G		3_prime_UTR_variant	20/25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251312 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727238

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: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.000111 Hom.: 0

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 11, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 28, 2020	This missense variant replaces tyrosine with cysteine at codon 2905 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/251312 chromosomes 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. -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Sharing Clinical Reports Project (SCRP)

May 01, 2012

- -

BRCA2-related cancer predisposition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 22, 2024

This missense variant replaces tyrosine with cysteine at codon 2905 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. Functional studies have shown this variant does not impact cell viability or increase drug sensitivity to cisplatin or PARP inhibitors (PMID: 32444794, 37922907), but does increase sensitivity to CBDCA (PMID: 32444794). This variant has not been reported in individuals affected with BRCA2-related cancer in the literature, but has been reported in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008698). This variant has been identified in 4/251312 chromosomes 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

May 11, 2015

This variant is denoted BRCA2 c.8714A>G at the cDNA level, p.Tyr2905Cys (Y2905C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 8942A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Tyr2905Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Tyr2905Cys occurs at a position that is conserved across species and is located in the DNA binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA2 Tyr2905Cys is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2022

ClinVar contains an entry for this variant (Variation ID: 96871). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs431825368, gnomAD 0.01%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2905 of the BRCA2 protein (p.Tyr2905Cys). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Uncertain	0.24	D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.3	N;N
REVEL	Pathogenic	0.65
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0020	D;D
Vest4		0.55
MutPred		0.58		Loss of phosphorylation at Y2905 (P = 0.0179);Loss of phosphorylation at Y2905 (P = 0.0179);
MVP		0.93
MPC		0.17
ClinPred		0.85	D
GERP RS		5.3
gMVP		0.60

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: rs431825368; hg19: chr13-32950888;