rs398122603

chr13-32370436-A-Gchr13-32370436-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000059.4(BRCA2):c.8366A>G(p.Tyr2789Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y2789H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 6.26

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 16 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.8366A>G	p.Tyr2789Cys	missense_variant	19/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.8366A>G	p.Tyr2789Cys	missense_variant	19/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251424 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461710 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727174

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Feb 12, 2008	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 27, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Aug 17, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 16, 2021	The p.Y2789C variant (also known as c.8366A>G), located in coding exon 18 of the BRCA2 gene, results from an A to G substitution at nucleotide position 8366. The tyrosine at codon 2789 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been reported in 1/1120 pediatric cancer patients, who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with acute lymphoblastic leukemia (Zhang J et al. N. Engl. J. Med., 2015 Dec;373:2336-2346). This amino acid position is not well 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 21, 2022	This missense variant replaces tyrosine with cysteine at codon 2789 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 not been reported in individuals affected with hereditary cancer in the literature and has been reported in an unaffected individual (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_008663). This variant has been identified in 1/251424 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

Jul 08, 2021

Variant summary: BRCA2 c.8366A>G (p.Tyr2789Cys) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251424 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8366A>G has been reported in the literature as a VUS of germline origin in at-least one individual with hypodiploid ALL (Zhang_2015) and as a presumed germline variant in the setting of Fibrolamellar hepatocellular carcinoma (Cornella_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Nov 01, 2022

The frequency of this variant in the general population, 0.000004 (1/251424 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual each with acute lymphoblastic leukemia (ALL) (PMID: 26580448 (2015)), and an individual with Fibrolamellar hepatocellular carcinoma (FLC) (PMID: 25557953 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 2789 of the BRCA2 protein (p.Tyr2789Cys). This variant is present in population databases (rs398122603, gnomAD 0.003%). This missense change has been observed in individual(s) with acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 91508). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	0.050
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Uncertain	0.40	D
MutationTaster	Benign	0.93	D;D
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.0080	D;D
Vest4		0.40
MutPred		0.60		Gain of disorder (P = 0.0483);Gain of disorder (P = 0.0483);
MVP		0.95
MPC		0.032
ClinPred		0.88	D
GERP RS		5.2
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs398122603; hg19: chr13-32944573; COSMIC: COSV66448228; COSMIC: COSV66448228;