rs80358730

chr13-32326272-A-Gchr13-32326272-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_000059.4(BRCA2):c.506A>G(p.Lys169Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000173 in 1,613,078 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K169E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:11
• Conservation: PhyloP100: 2.48

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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.1809983).
• BP6: Variant 13-32326272-A-G is Benign according to our data. Variant chr13-32326272-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 37941.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=7, Benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.506A>G	p.Lys169Arg	missense_variant	6/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.506A>G	p.Lys169Arg	missense_variant	6/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152186 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: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251168 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135806

Gnomad AFR exome AF: 0.0000617

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: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000183 AC: 268 AN: 1460892 Hom.: 0 Cov.: 31 AF XY: 0.000179 AC XY: 130 AN XY: 726808

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: 0.000223

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74354

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: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000180 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Apr 21, 2016	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 03, 2007	- -
Likely benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 17, 2015	- -

not provided Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 02, 2022	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 06, 2018	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	curation	Sema4, Sema4	Aug 03, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 23, 2021	Variant summary: BRCA2 c.506A>G (p.Lys169Arg) 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 5.6e-05 in 251168 control chromosomes, predominantly at a frequency of 0.00011 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 Syndrome (5.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.506A>G has been reported in the literature in as a VUS in settings of somatic and germline multigene panel testing in individuals with a wide variety of cancers, example, male prostate cancer, breast cancer, the cancer genome atlas (TGCA) cohort, ALL, low-grade serous carcinomas (LGSCs) (example, Kote-Jarai_2011, Davies_2018, Lu_2015, Zhang_2015, Zhang_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been reported in the BIC database (BRCA2 c.8537_8538delAG, p.Glu2846Glyfs; BRCA1 c.188T>A, p.Leu63X) and with a driver KRAS mutation, p.G12V in an individual with low-grade serous carcinomas (LGSCs) (Zhang_2021), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function (example, Biswas_2020). These results showed no damaging effect of this variant in a mouse embryonic stem cell-based functional assay examining the ability to rescue the lethality of Brca2 null mESC as well as sensitivity to six DNA damaging agents including ionizing radiation and a PARP inhibitor. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation with conflicting assessments and a predominant consensus towards a benign/likely benign (n=6) outcome (VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 06, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Fanconi anemia complementation group D1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

BRCA2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2024

The BRCA2 c.506A>G variant is predicted to result in the amino acid substitution p.Lys169Arg. This variant has been documented in the literature as a variant of uncertain significance in individuals undergoing a wide variety of cancer testing, but no additional data supports its pathogenicity (Kote-Jarai et al. 2011. PubMed ID: 21952622; Hondow et al. 2011. PubMed ID: 21702907). In silico splicing algorithms predict this variant will create a cryptic splice junction; however functional analysis of splicing indicated it does not alter splicing (Alamut Visual Plus v.1.6.1; Table S3b, Houdayer et al. 2012. PubMed ID: 22505045; Table S1, Wai et al. 2020. PubMed ID: 32123317). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/37941/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Breast and/or ovarian cancer Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 06, 2023

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.80	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.61	N;N
REVEL	Benign	0.14
Sift	Benign	0.048	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.35
MutPred		0.26		Loss of methylation at K169 (P = 0.0062);Loss of methylation at K169 (P = 0.0062);
MVP		0.85
MPC		0.024
ClinPred		0.063	T
GERP RS		2.7
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs80358730; hg19: chr13-32900409; COSMIC: COSV99061754;