rs80359189

chr13-32380131-T-Cchr13-32380131-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM1 PP3 BP6

The NM_000059.4(BRCA2):c.9242T>C(p.Val3081Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000136 in 1,612,824 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V3081F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8
• Conservation: PhyloP100: 5.68

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 2 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 14 uncertain in NM_000059.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834
• BP6: Variant 13-32380131-T-C is Benign according to our data. Variant chr13-32380131-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 38222.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9242T>C	p.Val3081Ala	missense_variant	24/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9242T>C	p.Val3081Ala	missense_variant	24/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250360 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135322

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: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1460624 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 726592

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74358

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000554 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19043619, 25479140, 32123317, 25348012, 28283652, 10923033, 29394989, 28873162, 31131559, 30254663, 31131967, 29884841) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2022	BRCA2: BP1, BS3:Supporting -

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Likely benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 27, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary breast ovarian cancer syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 02, 2021	The BRCA2 c.9242T>C (p.Val3081Ala) missense change has a maximum subpopulation frequency of 0.0033% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/13-32954268-T-C). Seven of seven in silico tools predict a deleterious effect of this variant on protein function, however an in vitro functional study reported that this variant results in an activity comparable to the wild type in homology-directed DNA repair (HDR) assays (BS3; PMID: 29394989). A large case control study of 41,890 European breast cancer patients and 41,607 European controls indicated that the variant is present in approximately equal proportions of cases and controls with an odds ratio of less than or equal to 1 (PMID: 28283652). This variant has been reported to co-occur with a pathogenic variant, BRCA2 c.8364G>A, p.Trp2788X (BP2; UMD database). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, BS3, BP2. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2020	Variant summary: BRCA2 c.9242T>C (p.Val3081Ala) results in a non-conservative amino acid change located in the OB3 fold (IPR015188) 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 2e-05 in 347936 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Though the variant, c.9242T>C, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and related tumor phenotypes, it was also found in several healthy controls (Grant_2015, Shimelis_2017, Zuntini_2018, Al Hannan_2019). Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.8364G>A, p.Trp2788X; in UMD), providing supporting evidence for a benign role. An in vitro functional study reported that this variant results in an activity comparable to the wild type in homology-directed DNA repair (HDR) assays (Guidugli_2018, Hart_2018). In addition, a recent multifactorial likelihood analysis predicted this variant to be Likely Benign (Parsons_2019). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as Likely benign (4x) or VUS (1x). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 08, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.11
Cadd	Uncertain	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	0.66	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Vest4		0.58
MutPred		0.72		Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP		0.94
MPC		0.17
ClinPred		0.87	D
GERP RS		5.5
gMVP		0.46

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: rs80359189; hg19: chr13-32954268;