chr13-32380079-G-T

Position:

• chr13-32380079-G-T

Variant summary

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

The NM_000059.4(BRCA2):​c.9190G>T​(p.Asp3064Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 2.30

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.9190G>T	p.Asp3064Tyr	missense_variant	24/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9190G>T	p.Asp3064Tyr	missense_variant	24/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74300

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 13, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 27, 2023	Observed in an individual with adenocarcinoma of the cecum and appendix (Maletzki et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate no damaging effect: ability to rescue cell lethality and lack of sensitivity to DNA-damaging drugs in a mouse embryonic stem cell (mESC)-based assay (Biswas et al., 2020); Also known as 9418G>T; This variant is associated with the following publications: (PMID: 12228710, 19043619, 29884841, 32377563, 30683709, 33293522) -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jul 19, 2021	This missense variant replaces aspartic acid with tyrosine at codon 3064 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). Complementation and drug sensitivity assays in mouse ES cells reported this variant to be functional (PMID: 33293522). This variant has been reported in an individual affected with colorectal cancer (PMID: 30683709). 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	May 31, 2023	The p.D3064Y variant (also known as c.9190G>T), located in coding exon 23 of the BRCA2 gene, results from a G to T substitution at nucleotide position 9190. The aspartic acid at codon 3064 is replaced by tyrosine, an amino acid with highly dissimilar properties. Utilizing a bioinformatics method that integrates information about protein sequence, conservation, and structure in a protein likelihood ratio, this alteration was predicted to be neutral (Karchin R et al. Cancer Inform 2008; 6:203-16). This alteration has been reported in an individual with early-onset colorectal cancer (Maletzki C et al. Oncologist, 2019 07;24:877-882). This alteration demonstrated behavior similar to wildtype in a mouse embryonic stem cell survival assay (Biswas K et al. NPJ Genom Med, 2020 Dec;5:52). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 11, 2019

Variant summary: BRCA2 c.9190G>T (p.Asp3064Tyr) results in a non-conservative amino acid change located in the BRCA2, OB3 domain (IPR015188) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251296 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9190G>T has been reported in the literature in individuals affected with Breast and Ovarian Cancer or suspected LS (Karchin_2008, Maletzki_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, no assertion criteria provided

clinical testing

Breast Cancer Information Core (BIC) (BRCA2)

Feb 20, 2004

- -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 14, 2023

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 14, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 3064 of the BRCA2 protein (p.Asp3064Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52773). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.64	D;D
MetaSVM	Benign	-0.32	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.027	D;D
Sift4G	Uncertain	0.043	D;D
Vest4		0.54
MutPred		0.45		Loss of disorder (P = 0.0244);Loss of disorder (P = 0.0244);
MVP		0.93
MPC		0.17
ClinPred		0.94	D
GERP RS		3.7
gMVP		0.41

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: rs80359177; hg19: chr13-32954216;