rs786201837

Positions:

• chr13-32337134-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_000059.4(BRCA2):​c.2779A>G​(p.Met927Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: -0.859

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1126802).
• BP6: Variant 13-32337134-A-G is Benign according to our data. Variant chr13-32337134-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184978.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=6}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.2779A>G	p.Met927Val	missense_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.2779A>G	p.Met927Val	missense_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.2410A>G	p.Met804Val	missense_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.2779A>G		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461574 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727074

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 09, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 28, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jun 08, 2023	This missense variant replaces methionine with valine at codon 927 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). Functional studies using a homology-mediated DNA repair assay that examines low-frequency spontaneous repair events and a yeast DNA repair assay have both shown this variant protein to be repair proficient (PMID: 21671020, 23328489). This variant has been reported in families and individuals affected with breast/ovarian cancer (PMID: 21671020, 23635950, 35402282). This variant has been reported in a multifactorial analysis as likely benign based in part to segregation and family history likelihood ratios (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. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 15, 2023	This missense variant replaces methionine with valine at codon 927 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). Functional studies using a homology-mediated DNA repair assay that examines low-frequency spontaneous repair events and a yeast DNA repair assay have both shown this variant protein to be repair proficient (PMID: 21671020, 23328489). This variant has been reported in families and individuals affected with breast/ovarian cancer (PMID: 21671020, 23635950, 35402282). This variant has been reported in a multifactorial analysis as likely benign based in part to segregation and family history likelihood ratios (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. -
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	Oct 25, 2023	The p.M927V variant (also known as c.2779A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 2779. The methionine at codon 927 is replaced by valine, an amino acid with highly similar properties. Two functional studies have used homologous recombination (HR) based assays to show that this alteration increases the rate of HR comparable to wild-type BRCA2 and is therefore likely non-pathogenic (Balia C et al. Breast Cancer Res Treat. 2011 Oct;129(3):1001-9; Spugnesi L et al. Mutagenesis. 2013 Mar;28(2):187-95). Balia et al also noted that the tumor from the individual with this alteration did not show loss of heterozygosity, and while the data was not shown, the authors mentioned that this variant did not segregate with disease in the family. This alteration has also been reported in two individuals from the same Serbian family, both with breast cancer (Dobricic J et al. J Hum Genet. 2013 Aug;58(8):501-7). Of note, this alteration is also designated as 3007A>G in published literature. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 03, 2023	Variant summary: BRCA2 c.2779A>G (p.Met927Val) results in a conservative amino acid change in 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 250872 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2779A>G has been reported in the literature as not co-segregating with disease in at-least one family affected with Hereditary Breast and Ovarian Cancer (HBOC) (example, Balia_2011) and in at-least two individuals from high risk families using an in-silico tool (Polyphen) as the basis of causality (Dobricic_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Balia_2011). These results showed no damaging effect of this variant on BRCA2 DNA repair activity in a yeast based experimental system. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=6; likely benign, n=2). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, pending independent corroboration of the reported neutral functional outcome by another independent study, the variant was classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial cancer of breast Benign:2

Likely benign, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 09, 2024	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BP5_SUP, PM2_SUP -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Nov 28, 2023

The BRCA2 c.2779A>G (p.Met927Val) variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 37415649 (2023), 35402282 (2022), 21671020 (2011)), 23635950 (2013)), and childhood leukemia (PMID: 31721781 (2019)). Functional studies indicate this variant has neutral effects on BRCA2 protein function (24323938 (2014), 23328489 (2013), 21671020 (2011)). 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 breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	0.022
DANN	Benign	0.34
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.065	N
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.15
Sift	Benign	0.20	T;T
Sift4G	Benign	0.30	T;T
Vest4		0.24
MutPred		0.28		Loss of phosphorylation at Y930 (P = 0.1138);Loss of phosphorylation at Y930 (P = 0.1138);
MVP		0.71
MPC		0.021
ClinPred		0.033	T
GERP RS		-2.1
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs786201837; hg19: chr13-32911271; COSMIC: COSV66461723; COSMIC: COSV66461723;