13-32362585-A-G

Variant names:

• chr13-32362585-A-G
• rs80359012
• NM_000059.4:c.7868A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H2623L) has been classified 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
• Publications: 19 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: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 10 benign, 25 uncertain in NM_000059.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32362585-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 922959.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 38123.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.7868A>G	p.His2623Arg	missense_variant	Exon 17 of 27	ENST00000380152.8	NP_000050.3

Ensembl

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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000410 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

Apr 12, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

reported as incidental finding in an individual without any tumor diagnosis_x000D_ Criteria applied: PS4_MOD, PM1, PM5, PM2_SUP, PP3 -

Dec 23, 2003

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 10, 2024

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:3

Nov 15, 2021

Sema4, Sema4

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

May 21, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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, 35736817). This variant has been detected in at least five individuals affected with breast cancer (PMID: 26023681, 33471991; Leiden Open Variation Database DB-ID BRCA2_000237, 36775216; 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. -

Sep 14, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Jun 27, 2023

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 23, 2018

Cancer Variant Interpretation Group UK, Institute of Cancer Research, London

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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). -

Oct 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; external communication, internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38123). Invitae Evidence Modeling incorporating data from in vitro 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. -

not provided Pathogenic:2

Dec 19, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Aug 15, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial cancer of breast Pathogenic:2

May 17, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PS3,PS4_MOD,PM1,PM5,PM2_SUP,PP3 -

Jan 27, 2021

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related cancer predisposition Pathogenic:1

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jan 31, 2014

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		9.2
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
Mutation Taster		=6/94	disease causing (ClinVar)

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: rs80359012; hg19: chr13-32936722;