rs1060502496

chr13-32337750-AA-GG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP6

The NM_000059.4(BRCA2):c.3395_3396delinsGG(p.Lys1132Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1132N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 4.24

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-32337750-AA-G is described in ClinVar as [Pathogenic]. Clinvar id is 1730938.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP6: Variant 13-32337750-AA-GG is Benign according to our data. Variant chr13-32337750-AA-GG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 409606.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.3395_3396delinsGG	p.Lys1132Arg	missense_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.3395_3396delinsGG	p.Lys1132Arg	missense_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 01, 2024	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. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear. -
Likely benign, criteria provided, single submitter	curation	University of Washington Department of Laboratory Medicine, University of Washington	Mar 23, 2023	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 07, 2020	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. -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 19, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2021	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. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060502496; hg19: chr13-32911887;