chr13-32333240-A-G

Variant names:

• chr13-32333240-A-G
• rs398122731
• NM_000059.4:c.1762A>G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM5 BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.1762A>G​(p.Asn588Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000806 in 1,612,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign 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. N588S) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:12
• Conservation: PhyloP100: 5.39

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.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32333241-A-G is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.2565603).
• BP6: Variant 13-32333240-A-G is Benign according to our data. Variant chr13-32333240-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 91757.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Uncertain_significance=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.1762A>G	p.Asn588Asp	missense_variant	Exon 10 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.1762A>G	p.Asn588Asp	missense_variant	Exon 10 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.1393A>G	p.Asn465Asp	missense_variant	Exon 10 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.1762A>G		non_coding_transcript_exon_variant	Exon 9 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000200 AC: 5 AN: 249790 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135186

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: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000856 AC: 125 AN: 1460406 Hom.: 0 Cov.: 35 AF XY: 0.0000812 AC XY: 59 AN XY: 726500

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: 0.000110

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74378

Gnomad4 AFR AF: 0.0000482

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: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

May 16, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21990134, 18824701, 27376475, 26898890) -

May 20, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Asn588Arg variant in BRCA2 has been reported in at least 5 individuals with BRCA2-associated cancers (Spearman 2008 PMID: 18824701, Kote-Jarai 2011 PMID: 21952622, Lu 2012 PMID: 22476429, Schenkel 2016 PMID: 27376475, Caminsky 2016 PMID: 26898890). It has also been identified in 0.005% (6/128542) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 91757). Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In silico functional studies provide some evidence that this variant does not impact protein function (Ikegami 2020 PMID: 32444794); however, these types of assays may not accurately represent biological function. In summary, while the clinical significance of this variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BP4. -

Aug 21, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 22, 2016

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Hereditary cancer-predisposing syndrome Benign:3

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -

Dec 14, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Jan 07, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2022

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Aug 07, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.1762A>G (p.Asn588Asp) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 249790 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1762A>G has been reported in the literature in individuals affected with breast/ovarian and prostate cancer (example, Lu_2012, Kote-Jari_2011, Spearman_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Additionally, multifactorial probability models support a "likely not pathogenic" (IARC class 2) outcome (Lindor_2012). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a high-throughput functional evaluation utilizing BRCA2-deficient cells and poly (ADP ribose) polymerase (PARP) inhibitors (example, Ikegami_2020). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus as likely benign (n=5). Based on the evidence outlined above, the variant was re-classified as likely benign. -

Mar 12, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group D1 Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Asn588Asp variant was identified in 2 of 3932 proband chromosomes (frequency: 0.0005) from individuals or families with breast and prostate cancer (Spearman 2008, Kote-Jarai 2011). The variant was identified in dbSNP (rs398122731) as “with likely benign allele”, ClinVar (classified as likely benign by Invitae, Color, GeneDx, Ambry Genetics, and three other submitters), LOVD 3.0 (observed 1x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 7 of 281,182 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 6 of 128,542 chromosomes (freq: 0.00005) and African in 1 of 24,676 chromosomes (freq: 0.00004), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The variant was identified by our laboratory as co-occurring with a pathogenic BRCA1 variant (c.5194-2A>G, p.?). The p.Asn588 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	23
DANN	Uncertain	1.0
Eigen	Benign	0.039
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.84	T
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.56	N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0090	D;D
Vest4		0.16
MutPred		0.31		Loss of MoRF binding (P = 0.0424);Loss of MoRF binding (P = 0.0424);
MVP		0.88
MPC		0.032
ClinPred		0.25	T
GERP RS		5.5
gMVP		0.12

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: rs398122731; hg19: chr13-32907377;