rs398122580

Positions:

• chr13-32355207-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.7354A>G​(p.Asn2452Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,134 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: -0.747

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07479626).
• BP6: Variant 13-32355207-A-G is Benign according to our data. Variant chr13-32355207-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 91475.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7354A>G	p.Asn2452Asp	missense_variant	14/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7354A>G	p.Asn2452Asp	missense_variant	14/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6985A>G	p.Asn2329Asp	missense_variant	14/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7354A>G		non_coding_transcript_exon_variant	13/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461134 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 726910

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

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	Sharing Clinical Reports Project (SCRP)	Dec 15, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Mar 29, 2023	The BRCA2 c.7354A>G (p.Asn2452Asp) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, and functional studies show this variant may behave similar to wild type (PMID: 21741379). This variant is absent in a database of women older than 70 years of age who have never had cancer (FLOSSIES database, https://whi.color.com/). This variant has been reported in an individual with a personal and/or family history of breast cancer (PMID: 25896959). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 24, 2016	Variant summary: The BRCA2 c.7354A>G (p.Asn2452Asp) variant located in the BRCA2 linker region (Warren_2011) causes a missense change with 3/4 in silico tools (SNPs&GO not captured here due to low reliability index) predict a benign outcome for this variant. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in an affected individual via a publication. A functional study indicates the variant could alter wild type function, however, the implications of these findings is not well established for tumorigenesis. Multiple clinical diagnostic laboratories/databases cite the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as "Variant of Uncertain Significance (VUS)." -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2020	This variant is associated with the following publications: (PMID: 25896959, 21741379) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 28, 2023	The p.N2452D variant (also known as c.7354A>G), located in coding exon 13 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7354. The asparagine at codon 2452 is replaced by aspartic acid, an amino acid with highly similar properties. Functional studies showed that cell lines transfected with the p.N2452D variant showed survival rates and apoptosis rates statistically similar to the wild type cell line after being dosed with DNA cross link-inducing drug cisplatin (CDDP) (Warren CR et al. Exp Cell Res. 2011 Sep; 317(15):2099-109). This variant has also been reported as a variant of unknown significance in one individual diagnosed with breast cancer (D'Argenio V et al. Clin Chim Acta. 2015 Jun; 446:221-5). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2452 of the BRCA2 protein (p.Asn2452Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or a family history of breast cancer (PMID: 21741379). ClinVar contains an entry for this variant (Variation ID: 91475). 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%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 21741379). 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	0.059
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	2.3
DANN	Uncertain	0.98
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.029	N
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.075	T;T
MetaSVM	Benign	-0.94	T
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.61	N;N
REVEL	Benign	0.020
Sift	Benign	0.030	D;D
Sift4G	Benign	0.28	T;T
Vest4		0.15
MutPred		0.13		Gain of helix (P = 0.0696);Gain of helix (P = 0.0696);
MVP		0.69
MPC		0.023
ClinPred		0.051	T
GERP RS		-0.40
gMVP		0.078

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: rs398122580; hg19: chr13-32929344;