NM_000059.4:c.4828G>A

Variant names:

• chr13-32339183-G-A
• rs80358705
• NM_000059.4:c.4828G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.4828G>A​(p.Val1610Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,613,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 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: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:12
• Conservation: PhyloP100: 0.721

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.073412).
• BP6: Variant 13-32339183-G-A is Benign according to our data. Variant chr13-32339183-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37927.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=4, Uncertain_significance=3}. Variant chr13-32339183-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.4828G>A	p.Val1610Met	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.4828G>A	p.Val1610Met	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4459G>A	p.Val1487Met	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.4828G>A		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152158 Hom.: 0 Cov.: 33

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000960 AC: 24 AN: 250074 Hom.: 0 AF XY: 0.0000812 AC XY: 11 AN XY: 135540

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: 0.000212

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000718 AC: 105 AN: 1461436 Hom.: 0 Cov.: 44 AF XY: 0.0000536 AC XY: 39 AN XY: 727054

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000882

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152158 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74340

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: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000882 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000124 AC: 15

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3 Benign:2

Aug 31, 2009

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

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. -

May 01, 2016

Department of Medical Genetics, University Hospital of North Norway

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Oct 31, 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. -

Jan 25, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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). -

May 19, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified Benign:3

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 12, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val1610Met variant in BRCA2 is classified as likely benign because it has been identified in 0.02% (24/113094) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 37927). 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. ACMG/AMP Criteria applied: BS1, BP4. -

Nov 23, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.4828G>A (p.Val1610Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-05 in 250074 control chromosomes, predominantly at a frequency of 0.00021 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (9.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.4828G>A has been reported in the literature in individuals affected with Breast and Ovarian Cancer (example, Lee_2008, Kote-Jarai_2011, Simard_2007, Caminsky_2016, Jarhelle_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least two known co-occurrences with other pathogenic variant(s) have been reported (UMD database-BRCA1 c.4327C>T, p.Arg1443*; BIC database-BRCA1 c.3481_3491delGAAGATACTAG, p.Glu1161_Ser1164?fs), providing supporting evidence for a benign role. Two recent reports from the CAGI5 (fifth Critical Assessment of Genome Interpretation) challenge have classified this variant as likely benign in a prediction protocol that includes assessment of the impact of this variant on splicing and protein function using four sets of predictors (Padilla_2019, Cline_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four have classified the variant as Benign/Likely Benign and two classified the variant as uncertain significance citing overlapping references utilized in the context of this evaluation. Based on the evidence outlined above, the variant was re-classified as benign. -

not provided Benign:2

Jul 29, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 18284688, 16905680, 26898890, 27495310, 25479140, 21952622, 25348012, 10923033) -

-

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.Val1610Met variant was identified in 6 of 8922 proband chromosomes (frequency: 0.0007) from individuals with hereditary breast and ovarian cancer and prostate cancer (Simard 2007, Caminsky 2016, Jarhelle 2016, Dolman 2013, Kote-Jarai 2011, Lee 2008). The variant was identified in dbSNP (rs80358705) as “with other allele”, in ClinVar (interpreted as "uncertain significance" by Sinai Health System and 3 others, "benign" Invitae and 2 others and "likely benign" by Ambry Genetics and 1 other), LOVD 3.0 (observed 2x) and UMD-LSDB (observed 3x). The variant was identified in control databases in 23 of 245,458 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 23 of 111,150 chromosomes (freq: 0.0002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. In the UMD-LSDB database, the variant co-occurred with a pathogenic BRCA1 variant (p.Arg1443*). Additionally, a clinical laboratory reported the variant occurred with another pathogenic BRCA1 variant (p.Glu1161fsX3). The p.Val1610 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. -

Breast and/or ovarian cancer Uncertain:1

Jan 17, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Uncertain significance

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. -

Hereditary breast ovarian cancer syndrome Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.9
DANN	Uncertain	0.99
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.047	N
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.073	T;T
MetaSVM	Benign	-0.91	T
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.58	N;N
REVEL	Benign	0.066
Sift	Benign	0.20	T;T
Sift4G	Benign	0.10	T;T
Vest4		0.19
MVP		0.67
MPC		0.024
ClinPred		0.044	T
GERP RS		-2.0
gMVP		0.15

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: rs80358705; hg19: chr13-32913320;