13-32344593-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_000059.4(BRCA2):c.6877T>C(p.Phe2293Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000133 in 1,425,056 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. F2293F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:3
• Conservation: PhyloP100: 5.79

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 -1 ACMG points.

• BP6: Variant 13-32344593-T-C is Benign according to our data. Variant chr13-32344593-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52216.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=8, Likely_benign=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.6877T>C	p.Phe2293Leu	missense_variant	12/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6877T>C	p.Phe2293Leu	missense_variant	12/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000683 AC: 17 AN: 248864 Hom.: 0 AF XY: 0.0000445 AC XY: 6 AN XY: 134966

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000497

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: 0.0000133 AC: 19 AN: 1425056 Hom.: 0 Cov.: 28 AF XY: 0.00000985 AC XY: 7 AN XY: 710936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000406

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: 0.0000169

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000227

ExAC AF: 0.0000495 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Aug 17, 2011	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 01, 2023	This missense variant replaces phenylalanine with leucine at codon 2293 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 1 individual affected with breast cancer and 1 unaffected individual (PMID: 15889636, 31331294). This variant has been identified in 17/248864 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 07, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Apr 12, 1999	- -

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 08, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2022	Observed in individuals with a personal or family history of breast cancer (Ruiz-Flores 2002, Quezada Urban 2018); Published functional studies demonstrate no damaging effect: No significant impact on cell growth or cisplatin sensitivity compared to wild type in an in vitro assay (Warren 2011); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as BRCA2 7105T>C; This variant is associated with the following publications: (PMID: 15889636, 12442275, 30262796, 21741379, 31331294) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 02, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 13, 2020	The BRCA2 c.6877T>C; p.Phe2293Leu variant (rs80358912) is reported in the literature in several individuals affected with breast cancer (Calderon-Garciduenas 2005, Quezada Urban 2018, Ruiz-Flores 2002). This variant is found in Latino population with an overall allele frequency of 0.05% (17/34230 alleles) in the Genome Aggregation Database. The phenylalanine at codon 2293 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, a peptide containing this variant exhibited apoptotic effects on cultured cells similar to a wildtype peptide (Warren 2002), although the physiological relevance of this assay is uncertain. Due to limited information, the clinical significance of the p.Phe2293Leu variant is uncertain at this time. References: Calderon-Garciduenas AL et al. Clinical follow up of mexican women with early onset of breast cancer and mutations in the BRCA1 and BRCA2 genes. Salud Publica Mex. 2005 Mar-Apr;47(2):110-5. Quezada Urban R et al. Comprehensive Analysis of Germline Variants in Mexican Patients with Hereditary Breast and Ovarian Cancer Susceptibility. Cancers (Basel). 2018 Sep 27;10(10). Ruiz-Flores P et al. BRCA1 and BRCA2 mutation analysis of early-onset and familial breast cancer cases in Mexico. Hum Mutat. 2002 Dec;20(6):474-5. Warren CR et al. A new assay for functional screening of BRCA2 linker region mutations identifies variants that alter chemoresistance to cisplatin. Exp Cell Res. 2011 Sep 10;317(15):2099-109. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 22, 2023	This missense variant replaces phenylalanine with leucine at codon 2293 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 1 individual affected with breast cancer and 1 unaffected individual (PMID: 15889636, 31331294). This variant has been identified in 17/248864 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 23, 2021	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. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2293 of the BRCA2 protein (p.Phe2293Leu). This variant is present in population databases (rs80358912, gnomAD 0.06%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12442275, 30262796, 34196900). ClinVar contains an entry for this variant (Variation ID: 52216). 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%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 21741379). 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 04, 2023

Variant summary: BRCA2 c.6877T>C (p.Phe2293Leu) 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 allele was found at a frequency of 7.2e-05 in 249144 control chromosomes, predominantly at a frequency of 0.0005 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (7.2e-05 vs 0.00075), allowing no conclusion about variant significance. c.6877T>C has been reported in the literature in individuals of Mexican descent who were affected with Hereditary Breast and Ovarian Cancer (Ruiz-Flores_2002, Calderon-Garciduenas_2005, Quezada_2018), however without strong evidence for causality (such as co-segregation data). These reports therefore, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant was also found in a healthy control of Latino origin (Zayas-Villanueva_2019). Co-occurrences with other pathogenic variants have been reported (in the BIC database: BRCA1 c.798_799delTT (p.Val266_Ser267ValLysfs); and in an internal LCA sample: BRCA2 c.6078_6079delAA (p.Glu2028fsX20)), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function evaluating cell survival and apoptotic index of stably transfected cell lines treated with cisplatin. These results showed no damaging effect of this variant (Warren 2011). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=7) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.44	T;T
MetaSVM	Uncertain	0.24	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.6	N;N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.023	D;D
Vest4		0.55
MutPred		0.47		Loss of stability (P = 0.0199);Loss of stability (P = 0.0199);
MVP		0.89
MPC		0.17
ClinPred		0.38	T
GERP RS		5.0
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs80358912; hg19: chr13-32918730;