rs606231398

chr13-32333283-G-GAchr13-32333283-GA-G

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):c.1813dup(p.Ile605AsnfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,601,314 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. G602G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:50 O:2
• Conservation: PhyloP100: 0.512

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 Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32333283-G-GA is Pathogenic according to our data. Variant chr13-32333283-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 37762.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.1813dup	p.Ile605AsnfsTer11	frameshift_variant	10/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.1813dup	p.Ile605AsnfsTer11	frameshift_variant	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151588 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: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000129 AC: 3 AN: 232106 Hom.: 0 AF XY: 0.00000793 AC XY: 1 AN XY: 126070

Gnomad AFR exome AF: 0.0000656

Gnomad AMR exome AF: 0.0000325

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000942

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000124 AC: 18 AN: 1449726 Hom.: 0 Cov.: 35 AF XY: 0.0000139 AC XY: 10 AN XY: 720972

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.0000239

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000902

Gnomad4 OTH exome AF: 0.0000669

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151588 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 73980

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: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:50 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:16

Pathogenic, criteria provided, single submitter	clinical testing	Genologica Medica	Jan 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Aug 26, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 02, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	University of Science and Technology Houari Boumediene, Laboratory of Molecular and Cellular Biology (LBCM)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	May 25, 2017	The c.1813dup (p.Ile605Asnfs*11) variant in the BRCA2 gene has been detected in multiple patients with breast and/or ovarian cancer [referred as 2034insA and 2041insA in PMID 9150150, 21324516, 22535016] and prostate cancer [PMID 21952622].This variant has been reported in four individuals from the ExAC database (http://exac.broadinstitute.org/variant/22-29091226-TA-T). This one bp duplication in exon 10 results in a frameshift and the creation of a premature stop codon. This variant is expected to result in a loss of function of the protein. It is thus classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Sep 27, 2023	PVS1, PM2, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Sep 22, 2023	Criteria applied: PVS1,PS4,PM5_STR -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This variant inserts 1 nucleotide in exon 10 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2034insA, 2040insA, 2041insA, 2041dupA, 2041_2042insA, c.1813insA and c.1806dupA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in a breast cancer case-control meta-analysis in 20 cases and 1 unaffected control, which is estimated to have an odds ratio for pathogenicity of OR=17.689 (95%CI 2.374 to 131.809; p-value<0.001) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001802) and also has been reported in individuals affected with breast, ovarian, pancreatic, prostate and neuroendocrine cancers (PMID: 9150150, 9667259, 18042939, 20104584, 21324516, 21952622, 22729890, 25072261, 28724667, 29433453) and suspected hereditary breast and ovarian cancer families (PMID: 11802209, 21232165, 24156927). In one family, this variant was reported in 11 women affected with breast cancer across three generations (PMID: 9150150). This variant also has been detected in two compound heterozygous individuals with a second pathogenic BRCA2 mutation who exhibited clinical features consistent with Fanconi anemia (PMID: 15070707, 21548014). Haplotype analysis suggests that this variant may be a founder mutation and is common in people of German ancestry (PMID: 9585613, 23199084). This variant has been identified in 3/232106 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, no assertion criteria provided	clinical testing	Institute of Human Genetics, Medical University Innsbruck	Feb 11, 2015	- -
Pathogenic, criteria provided, single submitter	literature only	Counsyl	May 08, 2014	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Oct 11, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

not provided Pathogenic:15

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Ile605AsnfsX11 variant was identified in 8 of 22770 proband chromosomes (frequency: 0.00035) from individuals or families with Breast, Ovarian, or Prostate cancer (Becker, 2012; Heidemann, 2012; Janavicius, 2010; Kote-Jarai, 2011; Schubert, 1997; Zhang, 2011). The variant was shown to segregate in at least nine affected individuals with breast cancer (Schubert, 1997; Heidemann, 2012). The variant was also identified in dbSNP (ID: rs80359306) “With pathogenic allele”, HGMD, the BIC database (75X with class 5 clinical importance), and UMD (18X as a causal variant). The c.1813dupA duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 605 and leads to a premature stop codon 11 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 19, 2022	PP5, PM2, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2020	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with hereditary breast and ovarian cancer (Frank 1998, Foretova 2004, Tai 2007, Kote-Jarai 2011, Becker 2012, Blay 2013, Pritzlaff 2017, Ibrahim 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 21952622, 22535016, 9150150, 15024741, 18489799, 28324225, 30715675, 21324516, 23683081, 20104584, 25685387, 26834852, 22729890, 27225637, 27167707, 28008555, 22382806, 28873162, 28503720, 28664449, 28651617, 25085752, 23199084, 29433453, 21232165, 15689453, 9667259, 9585613, 25072261, 18042939, 28831036, 28724667, 29909963, 30720863, 28843361, 30014164, 30702160, 30322717, 30309722, 30257646, 21548014, 15070707, 28726808, 31454914, 26689913, 32318955, 31447099, 29176636, 32581362) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 23, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 18, 2023	The BRCA2 c.1813dup (p.Ile605Asnfs*11) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in affected individuals with breast and/or ovarian cancer (PMIDs: 9150150 (1997), 21324516 (2011), 22729890 (2012), 28324225 (2017), 30257646 (2018), and 36169650 (2022)). In a large scale breast cancer association study, it was found in individuals with breast cancer as well as a control (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). It has also been reported in individuals with prostate cancer (PMIDs: 29433453 (2018) and 32606146 (2020)). Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 23, 2023	The BRCA2 c.1813dup; p.Ile605AsnfsTer11 variant (rs80359306), also known as 2041insA and 2034insA, is reported in the literature in several individuals with HBOC-related cancers (Becker 2012, Foretova 2004, Ibrahim 2018, Zhang 2011), and was demonstrated to segregate with disease in a large German family (Schubert 1997). This variant has also been reported in patients with prostate and other cancers (Ibrahim 2018, Kote-Jarai 2011). This variant is reported in ClinVar and is classified as pathogenic by an expert panel (Variation ID: 37762). This variant is only found on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Functional data indicate that cell lines derived from patients harboring the c.1813dup variant are more susceptible than wild-type to radiation induced chromosomal abnormalities (Becker 2012). Based on available information, the p.Ile605AsnfsTer11 variant is considered to be pathogenic. REFERENCES Becker et al. A 24-color metaphase-based radiation assay discriminates heterozygous BRCA2 mutation carriers from controls by chromosomal radiosensitivity. Breast Cancer Res Treat. 2012; 135(1): 167-175. PMID: 22729890. Foretova et al. BRCA1 and BRCA2 mutations in women with familial or early-onset breast/ovarian cancer in the Czech Republic. Hum Mutat. 2004 Apr; 23(4): 397-398. PMID: 15024741. Ibrahim M et al. Male BRCA mutation carriers: clinical characteristics and cancer spectrum. BMC Cancer. 2018 Feb 13;18(1):179. PMID: 29433453. Kote-Jarai et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011; 105(8): 1230-1234. PMID: 21952622. Schubert et al. BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. Am J Hum Genet. 1997; 60(5): 1031-1040. PMID: 9150150. Zhang et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011; 121(2): 353-357. PMID: 21324516. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	BRCA2: PVS1, PS4, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Sep 20, 2023	This variant has been identified by standard clinical testing. Breast-ovarian cancer, familial, susceptibility to, 2 -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary breast ovarian cancer syndrome Pathogenic:6

Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneKor MSA	Jan 01, 2020	This sequence change inserts one nucleotide in exon 10 of the BRCA2 mRNA (c.1813dupA), causing a frameshift after codon 605. This creates a premature translational stop signal 11 amino acid residues later (p.Ile605Asnfs*11) and is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular variant has been reported in individuals affected with breast, ovarian, and prostate cancer (PMID: 9150150, 21952622, 22535016). The mutation database ClinVar contains entries for this variant (Variation ID: 37762). -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 08, 2016	The p.Ile605fs variant in BRCA2 has been reported in >75 individuals with BRCA2- associated cancers (Breast Cancer Information Core (BIC) database), and segregat ed with disease in 7 affected relatives from 1 family (Schubert 1997). This vari ant has also been identified in 3/63362 European chromosomes by the Exome Aggreg ation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80359306); howev er, this frequency is low enough to be consistent with the frequency of heredita ry breast and ovarian cancer (HBOC) in the general population. The p.Ile605fs va riant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 605 and leads to a premature termination codon 11 amino acids downstream. This alteration is then predicted to lead to a truncate d or absent protein. Heterozygous loss of function of the BRCA2 gene is an estab lished disease mechanism for HBOC. In summary, this variant meets our criteria t o be classified as pathogenic for HBOC in an autosomal dominant manner based upo n segregation studies, absence from controls, and predicted impact to protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	This sequence change creates a premature translational stop signal (p.Ile605Asnfs*11) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 9150150, 21324516, 21952622, 22535016, 22729890). It has also been observed to segregate with disease in related individuals. This variant is also known as 1813insA, 2041insA, and 2034insA. ClinVar contains an entry for this variant (Variation ID: 37762). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 20, 2017	Variant summary: The BRCA2 c.1813dupA (p.Ile605AsnfsX11) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1842dupT/ p.Asn615X, c.1889delC/ p.Thr630fsX14, etc). One in silico tool predicts a damaging outcome for this variant. This variant was found in 8/227550 control chromosomes at a frequency of 0.0000352, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). This variant has been reported in numerous affected individuals/families and has been classified this variant as pathogenic by multiple clinical diagnostic laboratories/reputable databases. Functional study showed variant with diminished DNA double strand break repair capacity (Becker_2012). Taken together, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 21, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 25, 2021	The c.1813dupA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a duplication of A at nucleotide position 1813, causing a translational frameshift with a predicted alternate stop codon (p.I605Nfs*11). This mutation has been detected in multiple individuals with breast, ovarian and prostate cancer from HBOC kindreds (Foretova L et al. Hum. Mutat. 2004 Apr;23:397-8; Janaviius R. EPMA J. 2010 Sept;1:397-412; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Kote-Jarai Z et al. Br. J. Cancer. 2011 Oct;105:1230-4; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Ibrahim M et al. BMC Cancer. 2018 02;18:179; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; Mehemmai C et al. Pathol Oncol Res, 2020 Apr;26:715-726). In one study, this variant was reported in 20/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration, in compound heterozygosity with another BRCA2 mutation, was also reported in an individual with Fanconi anemia (Myers K et al. Pediatr. Blood Cancer. 2012 Mar;58:462-5). The c.1813dupA pathogenic mutation was reported in two unrelated probands with a personal and/or family history of breast/ovarian cancers and was shown to diminish DNA double strand break repair capacity in response to irradiation (Becker AA et al. Breast Cancer Res. Treat. 2012 Aug;135:167-75). Of note, this mutation is also referred to as 2041insA, 2034insA,and c.1806_1807insA in the published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 22, 2023	This variant inserts 1 nucleotide in exon 10 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 2034insA, 2040insA, 2041insA, 2041dupA, 2041_2042insA, c.1813insA and c.1806dupA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in a breast cancer case-control meta-analysis in 20 cases and 1 unaffected control, which is estimated to have an odds ratio for pathogenicity of OR=17.689 (95%CI 2.374 to 131.809; p-value<0.001) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001802) and has also been reported in individuals affected with breast, ovarian, pancreatic, prostate and neuroendocrine cancers (PMID: 9150150, 9667259, 18042939, 20104584, 21324516, 21952622, 22729890, 25072261, 28724667, 29433453) and suspected hereditary breast and ovarian cancer families (PMID: 11802209, 21232165, 24156927). In one family, this variant was reported in 11 women affected with breast cancer across three generations (PMID: 9150150). This variant also has been detected in two compound heterozygous individuals with a second pathogenic BRCA2 mutation who exhibited clinical features consistent with Fanconi anemia (PMID: 15070707, 21548014). Haplotype analysis suggests that this variant may be a founder mutation and is common in people of German ancestry (PMID: 9585613, 23199084). This variant has been identified in 3/232106 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	research	Academic Department of Medical Genetics, University of Cambridge	Jan 26, 2018	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. -

Familial cancer of breast Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 25, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 16, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 03, 2023	Criteria applied: PVS1,PS4,PM2_SUP -

Breast and/or ovarian cancer Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	CZECANCA consortium	Jun 11, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Jun 23, 2023	- -

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

Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 26, 2023	_x000D_ Criteria applied: PVS1, PS4, PM2_SUP -

Carcinoma of pancreas Pathogenic:1

Pathogenic, no assertion criteria provided

case-control

CZECANCA consortium

Mar 04, 2021

- -

Breast carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Sep 12, 2021

- -

BRCA2-related disorder Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Pathogenic and reported on 09-10-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant classified as Pathogenic and reported on 05-11-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

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: rs80359306; hg19: chr13-32907420;