13-32341020-A-G

Position:

• chr13-32341020-A-G

Variant summary

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

The NM_000059.4(BRCA2):​c.6665A>G​(p.Tyr2222Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,074 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). Synonymous variant affecting the same amino acid position (i.e. Y2222Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:6
• Conservation: PhyloP100: -0.237

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=0.34623215).
• BP6: Variant 13-32341020-A-G is Benign according to our data. Variant chr13-32341020-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52151.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=7}. Variant chr13-32341020-A-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6665A>G	p.Tyr2222Cys	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.6665A>G	p.Tyr2222Cys	missense_variant	11/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 250722 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135548

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: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461074 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 726782

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: 0.0000108

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 26, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 16, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 02, 2023	The p.Y2222C variant (also known as c.6665A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 6665. The tyrosine at codon 2222 is replaced by cysteine, an amino acid with highly dissimilar properties.This alteration was previously identified in a male with early onset prostate cancer but no family history of breast, ovarian, or prostate cancer (Edwards SM et al. Am. J. Hum. Genet. 2003 Jan;72:1-12). This alteration has also been reported in cohorts of individuals deemed high-risk for breast and/or ovarian cancer (Kurian AW et al. J. Clin. Oncol. 2008 Oct;26:4752-8; Azzollini J et al. Eur. J. Intern. Med., 2016 Jul;32:65-71; Pilato B et al. Genes Chromosomes Cancer, 2016 10;55:803-13). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 21, 2017	- -
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). -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2023	Observed in individuals with BRCA2-related cancers (Edwards et al., 2003; Azzollini et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 6893A>G; This variant is associated with the following publications: (PMID: 11241844, 18779604, 12474142, 27225819, 32377563, 31086113, 29884841, 31853058, 27062684, 31911673) -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 29, 2024	Variant summary: BRCA2 c.6665A>G (p.Tyr2222Cys) results in a non-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 consistent with its in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). The variant allele was found at a frequency of 1.6e-05 in 250722 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6665A>G has been reported in the literature in sequencing studies of individuals affected with early onset prostate cancer, individuals undergoing clinical genetic testing for BRCA1/2 genes, familial breast/ovarian cancer (example, Edwards_2001, Edwards_2003, Kurian_2008, Azzollini_2016, Pilato_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been reported in the UMD database (BRCA1 c.1380dup, p.Phe461IlefsX19), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27062684, 12474142, 11241844, 18779604, 27225819). ClinVar contains an entry for this variant (Variation ID: 52151). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jun 18, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	1.6
DANN	Benign	0.88
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.081	N
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.48
Sift	Benign	0.18	T;T
Sift4G	Benign	0.20	T;T
Vest4		0.77
MutPred		0.78		Loss of phosphorylation at Y2222 (P = 0.0614);Loss of phosphorylation at Y2222 (P = 0.0614);
MVP		0.72
MPC		0.025
ClinPred		0.020	T
GERP RS		-5.6
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397507875; hg19: chr13-32915157; COSMIC: COSV104701424;