rs397507313

chr13-32338017-C-Achr13-32338017-C-Gchr13-32338017-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000059.4(BRCA2):c.3662C>A(p.Ser1221Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. S1221C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 3.24

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 5 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 15 benign, 16 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.3662C>A	p.Ser1221Tyr	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.3662C>A	p.Ser1221Tyr	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2023	Identified in an individual with familial breast cancer (Meindl et al., 2002); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 3890C>A; This variant is associated with the following publications: (PMID: 26992456, 31131967, 11802209, 22193408, 9002670, 29884841, 32377563) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 18, 2019	- -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

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	Ambry Genetics	Feb 15, 2023	The p.S1221Y variant (also known as c.3662C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 3662. The serine at codon 1221 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration was detected in 1/989 hereditary breast and/or ovarian cancer probands from a German cohort (Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80). This amino acid position is highly 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	Apr 30, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 27, 2023

Variant summary: BRCA2 c.3662C>A (p.Ser1221Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3662C>A has been reported as a VUS in the literature in individuals affected with breast cancer or with family history of breast cancer (examples: Kleibova_2019, Meindl_2002). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.3700_3704delGTAAA, p.Val1234Glnfs), in at least one individual affected with unilateral female breast cancer (example: Kleiblova_2019), 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: 31050813, 11802209). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=6) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

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

Uncertain significance, no assertion criteria provided

clinical testing

Sharing Clinical Reports Project (SCRP)

Jan 15, 2010

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 12, 2023

This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 1221 of the BRCA2 protein (p.Ser1221Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 11802209). ClinVar contains an entry for this variant (Variation ID: 37851). 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	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.17	D
MutationTaster	Benign	0.95	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-5.7	D;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.025	D;D
Vest4		0.56
MutPred		0.81		Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP		0.93
MPC		0.18
ClinPred		0.99	D
GERP RS		5.8
gMVP		0.51

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: rs397507313; hg19: chr13-32912154;