13-32370438-A-T

Variant names:

• chr13-32370438-A-T
• rs80359081
• NM_000059.4:c.8368A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000059.4(BRCA2):​c.8368A>T​(p.Thr2790Ser) 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 benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2790A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 0.353
• Publications: 7 publications found

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]

BRCA2 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 19 benign, 22 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19428423).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8368A>T	p.Thr2790Ser	missense_variant	Exon 19 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8368A>T	p.Thr2790Ser	missense_variant	Exon 19 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7999A>T	p.Thr2667Ser	missense_variant	Exon 19 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*426A>T		non_coding_transcript_exon_variant	Exon 18 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*426A>T		3_prime_UTR_variant	Exon 18 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:3

Jul 07, 2000

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 19, 2023

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with serine at codon 2790 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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. This variant has not been identified 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. -

Jul 08, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:3

Jan 02, 2018

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with breast cancer (Lovejoy et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8596A>T; This variant is associated with the following publications: (PMID: 22632462, 19043619, 10923033, 12228710, 32377563, 29884841, 31853058) -

Jun 08, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In the published literature, this variant has been reported in and individual with a personal and family history of cancer from a large hereditary cancer multigene panel testing cohort (PMID: 31853058 (2020)) as well as reported as having uncertain significance based on protein likelihood ratio models (PMID: 19043619 (2008)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

May 01, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with serine at codon 2790 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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. This variant has not been identified 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. -

Jan 11, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified Uncertain:1

Apr 04, 2024

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BRCA2 c.8368A>T (p.Thr2790Ser) results in a conservative amino acid change located in the BRCA2, OB1 (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251450 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8368A>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with a likely pathogenic variant (scored internally) have been reported (BRCA2 c.8378G>A, p.Gly2793Glu) in 3 patients in the BIC database, providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 19043619, 22632462). ClinVar contains an entry for this variant (Variation ID: 52567). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Oct 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 2790 of the BRCA2 protein (p.Thr2790Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 52567). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	0.10
BayesDel_addAF	Benign	0.0053	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	14
DANN	Benign	0.93
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.76	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Benign	-0.91	T
PhyloP100		0.35
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.49	N;N
REVEL	Benign	0.22
Sift	Benign	0.60	T;T
Sift4G	Benign	0.51	T;T
Vest4		0.31
MutPred		0.36		Gain of disorder (P = 0.0487);Gain of disorder (P = 0.0487);
MVP		0.83
MPC		0.046
ClinPred		0.10	T
GERP RS		2.2
gMVP		0.27
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

dbSNP: rs80359081; hg19: chr13-32944575;