rs1060502432

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_000059.4(BRCA2):c.8169T>A(p.Asp2723Glu) 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 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. D2723G) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 0.976

Variant links:

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]

BRCA2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-32363370-A-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 13-32363371-T-A is Pathogenic according to our data. Variant chr13-32363371-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409493.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=5}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.8169T>A	p.Asp2723Glu	missense_variant	18/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.8169T>A	p.Asp2723Glu	missense_variant	18/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.7800T>A	p.Asp2600Glu	missense_variant	18/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*227T>A		non_coding_transcript_exon_variant	17/26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259 link	n.*227T>A		3_prime_UTR_variant	17/25	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251114

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135770

show subpopulations

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

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.:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 21, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 2723 of the BRCA2 protein (p.Asp2723Glu). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with prostate cancer (PMID: 31948886). ClinVar contains an entry for this variant (Variation ID: 409493). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 37713444). This variant disrupts the p.Asp2723 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11207042, 15290653, 16489001, 23961350, 24728189, 25452441). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2024	Variant summary: BRCA2 c.8169T>A (p.Asp2723Glu) results in a conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251114 control chromosomes. c.8169T>A has been reported in the literature in an individual affected with prostate cancer. Functional evidence reports the variant to be non-functional (Sahu_2023, Ikegami_2020). Other variants at the same codon have been classiifed as pathogenic by our lab (p.Asp2723His, p.Asp2723Gly). The following publications have been ascertained in the context of this evaluation (PMID: 32444794, 37713444, 31948886). ClinVar contains an entry for this variant (Variation ID: 409493). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	Jan 09, 2024	. According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PS3 (strong pathogenic): Reported by one calibrated study to affect protein function similar to pathogenic control variants (PMID:32444794) (PS3 met)., PM3 (supporting pathogenic): Found in FA patient, phase unknown, PP3 (supporting pathogenic): CADD:23.0 REVEL: 0.753 HCI prior:0.66 BayesDEL:0.422084 -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 24, 2024	The p.D2723E variant (also known as c.8169T>A), located in coding exon 17 of the BRCA2 gene, results from a T to A substitution at nucleotide position 8169. The aspartic acid at codon 2723 is replaced by glutamic acid, an amino acid with highly similar properties. Two other alterations at the same codon, p.D2723G (c.8168A>G) and p.D2723H (c.8167G>C) are functionally deleterious across multiple functional assays (Easton D et al. Am J Hum Genet. 2007;81:873-883; Farrugia DJ et al. Cancer Res. 2008 May; 68(9):3523-31; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8; Guidugli L et al. Cancer Res. 2013 Jan 1;73(1):265-75). The p.D2723E 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 et al. Science. 2002; 297(5588):1837-48; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 20, 2022	This missense variant replaces aspartic acid with glutamic acid at codon 2723 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported low relative viability after treatment with PARP inhibitors in BRCA2-null cells expressing this variant (PMID: 32444794). This variant has been reported in individuals affected with breast or prostate cancer, and in 1 unaffected individual (PMID: 31948886, 33471991; Leiden Open Variation Database DB-ID BRCA2_000804). Different variants affecting the same codon, c.8167G>A (p.Asp2723Asn), c.8167G>C (p.Asp2723His), c.8168A>T (p.Asp2723Val), and c.8168A>G (p.Asp2723Gly) are considered to be disease-causing (ClinVar variation ID: 485412, 52515, 140975, 38141, 52516), suggesting that Asp at this position is important for the protein function. This variant has been identified in 1/251114 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. -

Familial cancer of breast

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

DANN

Uncertain

0.99

Eigen

Uncertain

0.33

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.94

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.95

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.2

N;N

REVEL

Pathogenic

0.75

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.74

MutPred

0.94

Gain of catalytic residue at W2725 (P = 0.0774);Gain of catalytic residue at W2725 (P = 0.0774);

MVP

0.96

MPC

0.16

ClinPred

1.0

GERP RS

0.52

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.85

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over