rs80359024

chr13-32362681-A-Gchr13-32362681-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000059.4(BRCA2):c.7964A>G(p.Gln2655Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,846 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. Q2655H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12 U:2
• Conservation: PhyloP100: 9.22

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_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.908
• PP5: Variant 13-32362681-A-G is Pathogenic according to our data. Variant chr13-32362681-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52450.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=10, Uncertain_significance=1, Pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7964A>G	p.Gln2655Arg	missense_variant	17/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7964A>G	p.Gln2655Arg	missense_variant	17/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461846 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727222

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:12 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 10, 2024	This missense variant replaces glutamine with arginine at codon 2655 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported that this variant impacts BRCA2 function in a homology-mediated repair assay (PMID: 29394989). This variant has been detected in two individuals affected with breast cancer and absent in 53461 unaffected individuals in a breast cancer case-control meta-analysis (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000247). This variant also has been found in trans with a pathogenic truncation variant in BRCA2 in an individual diagnosed with Fanconi anemia (PMID: 20608899). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 06, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 31, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 25, 2023	Observed in individuals undergoing multi-gene panel testing based on a personal and/or family history of cancer, as well as in individuals with breast cancer in a case-control study (Li et al., 2020; Dorling et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate decreased homology directed repair activity (Guidugli et al., 2018; Hart et al., 2019; Iversen et al., 2022); Also known as c.8192A>G; This variant is associated with the following publications: (PMID: 19043619, 26064523, 11430722, 29394989, 29884841, 35665744, 31131967, 29158857, 31853058, 32377563, 12228710, 33471991, 20608899) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2022	PP4, PM2, PS2, PS3_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 17, 2021	This variant has been reported with another pathogenic BRCA2 variant in trans (on a different chromosome) in an individual affected with Fanconi Anemia (PMIDs: 11430722 (2001) and 20608899 (2010)). In addition, this variant was reported to have a damaging effect on homology-directed repair in a peer-reviewed experimental study (PMID: 29394989 (2018)). This variant has not been reported in large, multi-ethnic general populations. Variant is predicted to have a damaging effect on the protein and is located in a potentially critical domain of the protein. Based on the available information, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 10, 2019	- -

Familial cancer of breast Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 30, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 12, 2024	Criteria applied: PS3,PM3,PM2_SUP -

Hereditary cancer-predisposing syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 29, 2023	This missense variant replaces glutamine with arginine at codon 2655 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported that this variant impacts BRCA2 function in a homology-mediated repair assay (PMID: 29394989). This variant has been detected in two individuals affected with breast cancer and absent in 53461 unaffected individuals in a breast cancer case-control meta-analysis (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000247). This variant also has been found in trans with a pathogenic truncation variant in BRCA2 in an individual diagnosed with Fanconi anemia (PMID: 20608899). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 06, 2023	The p.Q2655R pathogenic mutation (also known as c.7964A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7964. The glutamine at codon 2655 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected in trans with a BRCA2 pathogenic nonsense mutation in an archived medulloblastoma sample from a deceased girl with Fanconi Anemia (Ruud E et al. Acta Paediatr. 2001 May;90:580-3; Bodd TL et al. Acta Paediatr. 2010 Nov;99:1741-3). This alteration is also defective in a homology directed DNA repair (HDR) assay (Guidugli L et al. Am. J. Hum. Genet. 2018 02;102(2):233-248). Based on internal structural analysis this alteration is likely to disrupt DSS1 binding and is predicted to be as destabilizing to the local structure as other known pathogenic variants (Yang H et al. Science 2002 Sep;297:1837-48; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 2655 of the BRCA2 protein (p.Gln2655Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fanconi anemia (PMID: 20608899). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This missense change has been observed to co-occur in individuals with a different variant in BRCA2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 52450). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be deleterious (Invitae). Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29394989, 29884841). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Pathogenic	0.82	D
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	N;N
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.84
MutPred		0.82		Gain of MoRF binding (P = 0.0106);Gain of MoRF binding (P = 0.0106);
MVP		0.97
MPC		0.17
ClinPred		0.98	D
GERP RS		5.7
gMVP		0.80

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: rs80359024; hg19: chr13-32936818;