chr13-32379802-A-T

Position:

• chr13-32379802-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM5 BP6

The NM_000059.4(BRCA2):​c.9006A>T​(p.Glu3002Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,024 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. E3002K) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 0.863

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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 17 uncertain in NM_000059.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32379800-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP6: Variant 13-32379802-A-T is Benign according to our data. Variant chr13-32379802-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52725.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9006A>T	p.Glu3002Asp	missense_variant	23/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9006A>T	p.Glu3002Asp	missense_variant	23/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460024 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726434

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: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	PM2(Supporting)+PP3(Supporting)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Jul 13, 2012	- -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 30, 2023	- -
Uncertain significance, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Mar 11, 2015	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 23, 2020	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 27, 2017	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Oct 19, 2016

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 16, 2017

This variant is denoted BRCA2 c.9006A>T at the cDNA level, p.Glu3002Asp (E3002D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 9234A>T. This variant has been reported to disrupt an exonic splicing enhancer (ESE) and to strengthen a cryptic acceptor site that is 51 nucleotides downstream of the canonical acceptor site, resulting in the production of both the canonical transcript (69%) as well as aberrant transcripts (31%) (Acedo 2012). Fackenthal et al. (2016) demonstrated that use of this cryptic acceptor site may be a naturally occurring transcript, observed at minor frequencies. BRCA2 Glu3002Asp was shown to have mild to moderate effects on BRCA2 and Filamin A interaction, cellular multinucleation, unresolved cytoplasmic bridges, and homology-directed DNA break repair (HDR) activity; a multifactorial likelihood model calculated its probability of neutrality as 0.94 (Mondal 2012, Guidugli 2013). BRCA2 Glu3002Asp was not observed in large population cohorts (Lek 2016). Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. BRCA2 Glu3002Asp 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 and internal data, it is unclear whether BRCA2 Glu3002Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	0.019
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.59	D;D
MetaSVM	Uncertain	0.21	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.79	N;N
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.58
MutPred		0.44		Loss of ubiquitination at K3004 (P = 0.0613);Loss of ubiquitination at K3004 (P = 0.0613);
MVP		0.88
MPC		0.14
ClinPred		0.98	D
GERP RS		-1.9
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs80359153; hg19: chr13-32953939;