13-32362585-A-G

Position:

• chr13-32362585-A-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7868A>G​(p.His2623Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,820 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 U:3
• 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]

BRCA2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956
• PP5: Variant 13-32362585-A-G is Pathogenic according to our data. Variant chr13-32362585-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 38123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7868A>G	p.His2623Arg	missense_variant	17/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7868A>G	p.His2623Arg	missense_variant	17/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7499A>G	p.His2500Arg	missense_variant	17/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7876A>G		non_coding_transcript_exon_variant	16/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461820 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727212

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: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 03, 2023	reported as incidental finding in an individual without any tumor diagnosis_x000D_ Criteria applied: PS4_MOD, PM1, PM5, PM2_SUP, PP3 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 10, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Dec 23, 2003	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Apr 12, 2010	- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 14, 2022	The p.H2623R pathogenic mutation (also known as c.7868A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7868. The histidine at codon 2623 is replaced by arginine, an amino acid with highly similar properties. Homology-directed DNA repair (HDR) assays have demonstrated this variant to be non-functional (Guidugli L et al. Am. J. Hum. Genet. 2018 02;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80). This variant is located in an important DNA binding functional domain of BRCA2 and was predicted to be deleterious by a computational probabilistic likelihood ratio model (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). Based on internal structural analysis, this alteration is expected to lead to significant destabilization of the helical domain, where several other pathogenic alterations are present (Yang H et al. Science. 2002 Sep;297:1837-48). This variant segregated with disease in multiple families (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 supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2022	This missense variant replaces histidine with arginine at codon 2623 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). This variant has been reported to impact BRCA2 function in a homology-directed repair assay and in the rescue of cell viability and PARP-inhibitor sensitivity in BRCA2-deficient cells (PMID: 29394989, 32444794, 33293522). This variant has been detected in at least four individuals affected with breast cancer (PMID: 26023681, 33471991; Leiden Open Variation Database DB-ID BRCA2_000237; Color internal data). 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 Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Nov 15, 2021	- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2023	Variant summary: BRCA2 c.7868A>G (p.His2623Arg) results in a non-conservative amino acid change located in the helical domain (IPR015252) that is part of the DNA binding domain (PMID: 22193408) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant was also predicted to be 'likely deleterious' by a protein likelihood ratio model (Karchin_2008). The variant was absent in 251280 control chromosomes in gnomAD. c.7868A>G has been reported in the literature in at-least three individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Kechin_2022, Foley_2015, Machakova_2019) and one reportedly unaffected 41 year old female (Foley_2015). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a deleterious outcome for the variant in a homology-directed DNA repair (HDR) assay (Guidugli_2018). This is further corroborated by another study reporting a likely pathogenic outcome based on sensitivity to platinum based chemotherapies and ADP poly (ADP-ribose) polymerase (PARP) inhibitors in a BRCA2 knockout human colorectal adenocarcinoma cell line (Ikegami_2020). The following publications have been ascertained in the context of this evaluation (PMID: 26023681, 29394989, 29884841, 33273034, 35736817, 32444794, 19043619, 36367610, 31409081). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic: n=2; likely pathogenic: n=6). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 2623 of the BRCA2 protein (p.His2623Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast or ovarian cancer (PMID: 26023681, 31409081; Invitae; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38123). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 29394989, 32444794, 33609447). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Nov 23, 2018	Data used in classification: The frequency of this variant is 0/138,632 individuals (tgnomAD) (PM2_mod). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.995 and an overall classification of pathogenic (PS3_strong). This variant is classified on ClinVar as Likely Pathogenic by accredited diagnostic USA laboratory Ambry Genetics (2017) (PP5_sup). Data not used in classification: There are conflicting in silico predictions of pathogenicity: AlignGVGD (class: C25), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (26.8) (PP3-sup). There are additional reports of this variant in UMD (2), BIC (3), and BRCA2 LOVD (1). -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 15, 2022	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMIDs: 31409081 (2019), 28888541 (2017), 26023681 (2015)). In addition, functional studies have indicated the variant has deleterious effects on homology-directed DNA repair (PMID: 33609447 (2021), 29394989 (2018)) and response to PARP inhibitors (PMID: 32444794 (2020)). Based on the available information, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2022	Observed in individuals with a personal or family history of breast and other cancers (Foley et al., 2015; Lilyquist et al., 2017; Machackova et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8096A>G; This variant is associated with the following publications: (PMID: 33609447, 26023681, 25782689, 23108138, 19043619, 28152038, 31409081, 29394989, 29884841, 32444794, 12228710, 28888541, 35736817, 32377563) -

Familial cancer of breast Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 27, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 17, 2023	Criteria applied: PS3,PS4_MOD,PM1,PM5,PM2_SUP,PP3 -

BRCA2-related cancer predisposition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 27, 2024

This missense variant replaces histidine with arginine at codon 2623 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). This variant has been reported to impact BRCA2 function in a homology-directed repair assay and in the rescue of cell viability and PARP-inhibitor sensitivity in BRCA2-deficient cells (PMID: 29394989, 32444794, 33293522). This variant has been detected in at least four individuals affected with breast cancer (PMID: 26023681, 33471991; Leiden Open Variation Database DB-ID BRCA2_000237; Color internal data). 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 Pathogenic. -

not specified Uncertain:1

Uncertain significance, no assertion criteria provided

research

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Jan 31, 2014

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2, p.His2623Arg variant was identified in dbSNP (ID: rs80359012) “With likely pathogenic allele”, LOVD ,the ClinVar database (classified as a “likely pathogenic” variant by the Sharing Clinical Reports Project, derived from Myriad reports and Ambry Genetics; as “uncertain significance” by the BIC), GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (1X, classified as “unknown significance” by a clinical laboratory), the BIC database (3X with unknown clinical importance), and UMD (1X as a variant of unknown significance). The p.His2623 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.His2623 variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. A computational study by Karchin (2008) have suggested that p.His2623Arg is likely deleterious variant with likelihood ratio of 17.554 in favour of protein loss of function. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	0.95	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.96
MutPred		0.84		Gain of MoRF binding (P = 0.0436);Gain of MoRF binding (P = 0.0436);
MVP		0.96
MPC		0.17
ClinPred		0.98	D
GERP RS		5.7
gMVP		0.90

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: rs80359012; hg19: chr13-32936722;