13-32340586-G-C

Position:

• chr13-32340586-G-C

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.6231G>C​(p.Lys2077Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000658 in 1,610,380 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).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:6
• Conservation: PhyloP100: 0.656

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]

BRCA2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a repeat BRCA2 8 (size 34) in uniprot entity BRCA2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.24803314).
• BP6: Variant 13-32340586-G-C is Benign according to our data. Variant chr13-32340586-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135809.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6231G>C	p.Lys2077Asn	missense_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6231G>C	p.Lys2077Asn	missense_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.5862G>C	p.Lys1954Asn	missense_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6231G>C		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152174 Hom.: 0 Cov.: 32

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: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000117 AC: 29 AN: 248688 Hom.: 0 AF XY: 0.000149 AC XY: 20 AN XY: 134546

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: 0.000962

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000679 AC: 99 AN: 1458088 Hom.: 0 Cov.: 44 AF XY: 0.000102 AC XY: 74 AN XY: 725040

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: 0.00111

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74464

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 24, 2022	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	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 06, 2023	This missense variant replaces lysine with asparagine at codon 2077 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 5 individuals affected with breast and/or ovarian cancer, 1 individual affected with prostate cancer, and in 2 unaffected individuals (PMID: 28993434, 29470806, 29785135, 33471991; Leiden Open Variation Database DB-ID BRCA2_003775, 36259290 , 37277882). This variant has been identified in 29/248688 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 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 16, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 14, 2023	Variant summary: BRCA2 c.6231G>C (p.Lys2077Asn) results in a non-conservative amino acid change located in the BRCA2 repeat (IPR002093) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00012 in 249782 control chromosomes (gnomAD, Wen_2018), predominantly at a frequency of 0.00096 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.28 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.6231G>C has been reported in the literature in individuals affected with Breast/Ovarian Cancer (e.g. Kurian_2008, Singh_2018, Sirisena_2020, Dorling_2021) and Prostate cancer (Satapathy_2023) without evidence for causality. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function, showing that the variant was able to rescue Brca2-deficient mouse embryonic stem cells exposed to DNA damaging agents (Sirisena_2020). The following publications have been ascertained in the context of this evaluation (PMID: 18779604, 36259290, 29470806, 32393398, 28993434, 33471991). Nine ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and four as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 23, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces lysine with asparagine at codon 2077 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 5 individuals affected with breast and/or ovarian cancer, 1 individual affected with prostate cancer, and in 2 unaffected individuals (PMID: 28993434, 29470806, 29785135, 33471991; Leiden Open Variation Database DB-ID BRCA2_003775, 36259290 , 37277882). This variant has been identified in 29/248688 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. -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 11, 2022

Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Kurian et al., 2008; Mannan et al., 2016; Shah et al., 2018; Singh et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: comparable to wild-type in ability to rescue cell lethality and lack of response to DNA-damaging agents, as measured in mouse embryonic stem cell-based functional assay (Sirisena et al., 2020); Also known as 6459G>C; This variant is associated with the following publications: (PMID: 18779604, 35464868, 26911350, 32393398, 28726806, 9002670, 22193408, 29470806, 28993434, 29785135) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	0.071
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.25	T;T
MetaSVM	Uncertain	-0.043	T
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.011	D;D
Vest4		0.43
MutPred		0.85		Loss of ubiquitination at K2077 (P = 0.0199);Loss of ubiquitination at K2077 (P = 0.0199);
MVP		0.93
MPC		0.074
ClinPred		0.23	T
GERP RS		1.5
gMVP		0.58

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: rs541826447; hg19: chr13-32914723;