Submissions for variant NM_000059.4(BRCA2):c.3395_3396delinsGG (p.Lys1132Arg)

dbSNP: rs1060502496

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000472802	SCV000549876	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508164	SCV000600549	uncertain significance	not specified	2016-10-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563729	SCV000661240	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-28	criteria provided, single submitter	clinical testing	The c.3395_3396delAAinsGG variant (also known as p.K1132R), located in coding exon 10 of the BRCA2 gene, results from the deletion of AA and insertion of GG from nucleotide positions 3395 to 3396. The lysine at codon 1132 is replaced by arginine, an amino acid with highly similar properties. A similar alteration, c.3395A>G (p.K1132R), was identified in a Japanese breast cancer patient from Hawaii (Carney ME et al. Hawaii Med J. 2010 Nov;69(11):268-71) and in a familial breast cancer patient from Sardinia (Palomba G et al. BMC Cancer. 2009 Jul 20;9:245). This amino acid position is well conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000563729	SCV000683553	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-07	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 1132 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. A similar variant with the same protein change, c.3395A>G(p.Lys1132Arg), has been reported in individuals with breast cancer (PMID: 19619314, 1901676, 21218378, 30287823) but does not show significant association with disease (PMID: 30287823). This variant has not been identified 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	RCV000508164	SCV000918843	likely benign	not specified	2021-11-20	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3395_3396delinsGG (p.Lys1132Arg) variant involves the alteration of a dinucleotide sequence (AA>GG) where the first nucleotide (i.e. c.3395A>G) is conserved and leads to the same protein level change as the variant of interest (p.Lys1132Arg), however the second nucleotide is non-conserved and an A > G substitution (c.3396A>G, p.Lys1132Lys) is observed in the population as a common, benign polymorphism, with an overall minor allele frequency of ~0.3. p.Lys1132Arg results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant is located in the BRC repeat region between the first and second repeat; this region is involved in the binding of RAD51 (InterPro). c.3395_3396delinsGG (p.Lys1132Arg) and c.3395A>G (p.Lys1132Arg) both are absent in 281716 control chromosomes in gnomAD database. However, the frequency for c.3395A>G as reported within Japanese control individuals in the other databases and publications is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Japanese origin. c.3395_3396delinsGG has not, to our knowledge, been reported in affected individuals via publications. However, a single nucleotide alteration c.3395A>G (p.Lys1132Arg) has been reported in individuals affected with breast and ovarian cancer (example, Sugano 2008, Palomba 2009, Carney 2010, Ahmadloo 2017, Momozawa_2018), but was also found in healthy controls (example, Ahmadloo 2017, Momozawa_2018). These report(s) 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. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000563729	SCV003847514	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).