chr13-32363244-C-G

Position:

• chr13-32363244-C-G

Variant summary

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

The NM_000059.4(BRCA2):​c.8042C>G​(p.Thr2681Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,904 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. T2681A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:1
• Conservation: PhyloP100: 2.53

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8042C>G	p.Thr2681Arg	missense_variant	18/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8042C>G	p.Thr2681Arg	missense_variant	18/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152164 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461740 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74326

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 13, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 14, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces threonine with arginine at codon 2681 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). A functional study in mouse embryonic stem cells showed that this variant did not impact cell viability or drug sensitivity (PMID: 33293522). This variant has been reported in individuals with a personal or family history of breast or ovarian cancer (PMID: 18824701, 22476429) and in a multifactorial analysis with tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.690, 1.102 and 0.858, respectively (PMID: 31131967). 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. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 12, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2023	Published functional studies suggest no impact on function: performed similar to wild type in cell survival and drug-sensitivity assays (Biswas et al., 2020); Observed in individuals with a personal or family history including breast and/or ovarian cancer (Lu et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8270C>G; This variant is associated with the following publications: (PMID: 18951461, 18824701, 28339459, 29884841, 31853058, 32377563, 31131967, 12228710, 22476429, 33293522) -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 03, 2023	The p.T2681R variant (also known as c.8042C>G), located in coding exon 17 of the BRCA2 gene, results from a C to G substitution at nucleotide position 8042. The threonine at codon 2681 is replaced by arginine, an amino acid with similar properties. In another study, this variant was seen in 1/146 patients with breast cancer from high risk families, with at least two first- and second-degree relatives diagnosed with breast and/or ovarian cancer (Lu W et al. Fam. Cancer. 2012 Sep;11(3):381-5). A study utilizing a splicing reporter minigene assay found this alteration to have a weak impact on splicing (Fraile-Bethencourt E et al. PLoS Genet., 2017 Mar;13:e1006691). This variant was found to be functional in a mouse embryonic stem cell complementation and drug sensitivity assay (Biswas K et al. NPJ Genom Med 2020 Dec;5(1):52). 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	Nov 30, 2023	This missense variant replaces threonine with arginine at codon 2681 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). A functional study in mouse embryonic stem cells showed that this variant did not impact cell viability or drug sensitivity (PMID: 33293522). This variant has been reported in individuals with a personal or family history of breast or ovarian cancer (PMID: 18824701, 22476429) and in a multifactorial analysis with tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 0.690, 1.102 and 0.858, respectively (PMID: 31131967). 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 30, 2023

Variant summary: BRCA2 c.8042C>G (p.Thr2681Arg) 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 was absent in 251192 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8042C>G has been reported in the literature in individuals affected with breast cancer (example, Spearman_2008, Lu_2012), but has also been reported at a carrier frequency of 0.0001365 in a cohort of European American women over the age of 70 with no history of cancer (FLOSSIES dataset). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variants have been observed at our laboratory (CHEK2 c.283C>T, p.Arg95X; BRCA2 c.1755_1759delGAAAA, p.Lys585AsnfsX3), providing supporting evidence for a benign role. One study showed that this variant has a weak impact on splicing, with the canonical transcript at approximately 97.7% (Fraile-Bethencourt_BRCA2_PLOS_2017). Additionally, one functional study showed no damaging effect of this variant by cell survival and drug sensitivity (Biswas_2020). The following publications have been ascertained in the context of this evaluation (PMID: 33293522, 28339459, 22476429, 18824701). Eight ClinVar submitters have assessed this variant since 2014: seven classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Fanconi anemia complementation group D1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Oct 14, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 29, 2024

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	0.29	D
MutationTaster	Benign	0.83	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.7	N;N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.013	D;D
Vest4		0.58
MutPred		0.50		Gain of MoRF binding (P = 0.0116);Gain of MoRF binding (P = 0.0116);
MVP		0.89
MPC		0.16
ClinPred		0.94	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.70

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: rs587782519; hg19: chr13-32937381;