Submissions for variant NM_000059.4(BRCA2):c.3861TAA[1] (p.Asn1288del)

dbSNP: rs276174837

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000210490	SCV000266792	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This variant, c.3864_3866del, results in the deletion of 1 amino acid(s) of the BRCA2 protein (p.Asn1288del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with a family history of breast and/or ovarian cancer (PMID: 21232165, 22366370). This variant is also known as c.3863delTAA. ClinVar contains an entry for this variant (Variation ID: 126027). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pathology and Molecular Medicine, Queen's University	RCV000496508	SCV000588091	uncertain significance	not specified	2017-04-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000509900	SCV000608016	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-11	criteria provided, single submitter	clinical testing	The c.3864_3866delTAA variant (also known as p.N1288del) is located in coding exon 10 of the BRCA2 gene. This variant results from an in-frame TAA deletion at nucleotide positions 3864 to 3866. This results in the in-frame deletion of an asparagine at codon 1288. This variant has been reported in a Croatian HBOC family with no further details provided about the affected members in the family (Levanat S et al Gene 2012 498(2):169-76), in 1/115 healthy Croatian women between the ages of 65 and 100 years with no family history of cancer (Cvok ML et al. Clin. Chem. Lab. Med. 2008 ;46(10):1376-83), and in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). In addition, this alteration (designated c.3863delTAA) has been reported in 2/208 probands from Slovenian breast and/or ovarian cancer families and 0/80 healthy controls (Stegel V et al. BMC Med Genet, 2011 Jan;12:9). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneKor MSA	RCV000509900	SCV000821937	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000210490	SCV000838791	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758887	SCV000887801	uncertain significance	not provided	2017-12-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000509900	SCV000903466	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-10	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid in the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two families affected with breast and/or ovarian cancer, with no details provided about the affected individuals (PMID: 21232165, 22366370). This variant has been identified in 1/197174 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000496508	SCV000916920	uncertain significance	not specified	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3864_3866delTAA (p.Asn1288del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 5.1e-06 in 197484 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3864_3866delTAA has been reported in the literature in individuals affected with or being tested for Hereditary Breast And Ovarian Cancer Syndrome (Levanat_2012, Stegel_2011, Tsaousis_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Eight submitters classified the variant as VUS while one classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000113232	SCV001139076	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000113232	SCV001367075	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-02-21	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2,PM4.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001257273	SCV001433817	uncertain significance	Microprolactinoma	2020-02-21	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PM1,PM2,PP3,PP4,PP5. This variant was detected in heterozygous state.
GeneDx	RCV000758887	SCV003842467	uncertain significance	not provided	2023-03-14	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; Observed in individuals with a personal and/or family history of breast and/or other cancers (Levanat et al., 2012; Tsaousis et al., 2019; Li et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on protein structure/function; Also known as 4092_4094delTAA; This variant is associated with the following publications: (PMID: 22366370, 31131967, 18844490, 21232165, 31853058, 31159747)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492435	SCV004240308	uncertain significance	Breast and/or ovarian cancer	2023-05-24	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113232	SCV000146319	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-12-17	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000758887	SCV001978579	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000758887	SCV001980305	uncertain significance	not provided		no assertion criteria provided	clinical testing