rs80358842

chr13-32340413-G-Achr13-32340413-G-Cchr13-32340413-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BP6

The NM_000059.4(BRCA2):c.6058G>A(p.Glu2020Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,613,490 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E2020E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:5
• Conservation: PhyloP100: 3.87

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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39659533).
• BP6: Variant 13-32340413-G-A is Benign according to our data. Variant chr13-32340413-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126088.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=6}. Variant chr13-32340413-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6058G>A	p.Glu2020Lys	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6058G>A	p.Glu2020Lys	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461376 Hom.: 0 Cov.: 47 AF XY: 0.0000206 AC XY: 15 AN XY: 726998

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152114 Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6 AN XY: 74308

Gnomad4 AFR AF: 0.0000483

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: 0.0000588

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 04, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 23, 2023	This missense variant replaces glutamic acid with lysine at codon 2020 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant has no impact on sensitivity to PARP inhibitors (PMID: 32444794). This variant has been reported in individuals affected with breast and/or ovarian cancer, and prostate cancer (PMID: 11698567, 22476429, 29470806, 31214711). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 4/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001098). This variant has been reported in a multifactorial analysis with segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.1762, 0.9523, 1.0757 and 0.786, respectively (PMID: 31131967). This variant has been identified in 1/245768 chromosomes 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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jun 12, 2000	- -
Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 28, 2009	- -

not provided Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 12, 2023	The frequency of this variant in the general population, 0.000059 (4/67974 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with and at high risk for breast and/or ovarian cancer (PMIDs: 11698567 (2001), 22476429 (2012), 29470806 (2018), and 33471991 (2021); LOVD3 Shared (https://databases.lovd.nl/shared/)), as well as in an individual affected with glioblastoma multiforme (PMID: 26689913 (2015)). One functional study using a colorectal cancer cell line reports this variant likely does not affect the homology directed repair function of BRCA2 protein, however it is not clear if these results are reproducible in other cell lines (PMID: 32444794 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2023	Published functional studies demonstrate no damaging effect: variant classified as likely normal in a PARP inhibitor assay (Ikegami et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 6286G>A; This variant is associated with the following publications: (PMID: 11698567, 26689913, 22476429, 31131967, 29470806, 32444794) -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 28, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 14, 2023	This missense variant replaces glutamic acid with lysine at codon 2020 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown that this variant has no impact on sensitivity to PARP inhibitors (PMID: 32444794). This variant has been reported in individuals affected with breast and/or ovarian cancer, and prostate cancer (PMID: 11698567, 22476429, 29470806, 31214711). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 2/60466 cases and 4/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001098). This variant has been reported in a multifactorial analysis with segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.1762, 0.9523, 1.0757 and 0.786, respectively (PMID: 31131967). This variant has been identified in 1/245768 chromosomes 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 01, 2019

Variant summary: BRCA2 c.6058G>A (p.Glu2020Lys) 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 was absent in 250910 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6058G>A has been reported in the literature in individuals with a personal or family history of breast/ovarian cancer (Hartmann_2001, Lu_2012, Singh_2018), however, with limited information (i.e. lack of co-occurrence and cosegregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported (BRCA1 c.4206_4207delTA, p.His1402GlnfsX11; UMD), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Glu2020Lys variant was identified in 1 of 352 proband chromosomes (frequency: 0.003) from individuals or families with breast cancer (Hartmann 2001). The variant was also identified in dbSNP (ID: rs80358842) “With uncertain significance, untested allele”, Exome Aggregation Consortium (ExAC) database, COSMIC, the ClinVar database (classified as an uncertain significance variant by the Sharing Clinical Reports Project, derived from Myriad reports; BIC, Ambry Genetics and GeneDx), the BIC database (2X with unknown clinical importance), and UMD (4X as an unclassified variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.4206_4207delTA (p.His1402GlnfsX11)), increasing the likelihood that the p.Glu2020Lys variant does not have clinical significance. This variant was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 1 of 66330 chromosomes (1 individual) from a population of European (Non-Finnish) individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease.The p.Glu2020 residue is 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 computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of unknown significance. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.40	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.22
Sift	Uncertain	0.023	D;D
Sift4G	Benign	0.071	T;T
Vest4		0.50
MutPred		0.34		Gain of MoRF binding (P = 0.0075);Gain of MoRF binding (P = 0.0075);
MVP		0.84
MPC		0.068
ClinPred		0.83	D
GERP RS		1.4
gMVP		0.20

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: rs80358842; hg19: chr13-32914550; COSMIC: COSV66450746;