rs276174926

Positions:

• chr13-32397009-GC-CT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PS1 PM2 BP6

The NM_000059.4(BRCA2):​c.9613_9614delGCinsCT​(p.Ala3205Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Pathogenicin Lovd.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:4 O:1
• Conservation: PhyloP100: 0.310

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PS1: Transcript NM_000059.4 (BRCA2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 13-32397009-GC-CT is Benign according to our data. Variant chr13-32397009-GC-CT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 52875.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=8, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9613_9614delGCinsCT	p.Ala3205Leu	missense_variant		ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9613_9614delGCinsCT	p.Ala3205Leu	missense_variant		5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9244_9245delGCinsCT	p.Ala3082Leu	missense_variant		1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1671_*1672delGCinsCT		non_coding_transcript_exon_variant	25/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1671_*1672delGCinsCT		3_prime_UTR_variant	25/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 13, 2022	The frequency of this variant in the general population, 0.000058 (2/34590 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 33471991 (2021), 25777348 (2015), 10717622 (2000)), prostate cancer (PMID: 25111659 (2014)), and pancreatic cancer (PMID: 34034685 (2021)). It has also been reported in unaffected individuals (PMID: 33471991 (2021), 30883245 (2019), 24728327 (2014)). In addition, this variant was also reported to cause minimal exon 26 skipping in the BRCA2 gene (PMID: 20215541 (2010)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2024	Observed in individuals with a personal or family history of breast, ovarian, pancreatic, or prostate cancer (PMID: 10717622, 25111659, 25777348, 30883245, 32438681, 36011273, 35402282, 35127508, 39062721); Published functional studies demonstrate no damaging effect on splicing (PMID: 19471317, 20215541); In silico analysis indicates that this variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9841_9842delinsCT; This variant is associated with the following publications: (PMID: 35753294, 25111659, 24728327, 10717622, 25777348, 20215541, 19471317, 25382762, 21120943, 31209999, 33471991, 34572941, 32438681, 30883245, 36011273, 34933735, 35402282, 35127508, 39062721) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 20, 2021	- -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:2 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Department of Medical and Surgical Sciences, University of Bologna	Sep 01, 2023	BP1(Strong)+BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042) -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	an indel in the BRCA2 gene (c.9613_9614delGCinsCT) which results in the substitution of Leucine for Alanine at amino acid position 3205. This mutation is considered as a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 29, 2022	The c.9613_9614delGCinsCT variant (also known as p.A3205L), located in coding exon 25 of the BRCA2 gene, results from the deletion of two nucleotides (GC) and the insertion of two nucleotides (CT) at nucleotide positions 9613 to 9614. The alanine at codon 3205 is replaced by leucine, an amino acid with similar properties. This variant has been reported in individuals with hereditary breast, ovarian, and/or prostate cancer, but its clinical significance has been reported as uncertain in several studies (Malone KE et al. Cancer. 2000 Mar 15;88:1393-402; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32:325-34; Maier C et al. Prostate. 2014 Oct;74:1444-51; El Saghir NS et al. Oncologist. 2015 Apr;20:357-64; Abe T et al. J. Clin. Oncol., 2019 05;37:1070-1080; Santonocito C et al. Cancers (Basel), 2020 May;12). In an ancestrally diverse cohort of 681 healthy individuals who underwent genome sequencing, this variant was detected in 1/331 Europeans (Bodian DL et al. PLoS One. 2014 Apr 11;9:e94554). A RT-PCR splicing assay showed that this alteration did not show a remarkable splicing consequence, producing only minimal skipping of coding exon 25 (Sanz DJ et al. Clin. Cancer Res. 2010 Mar 15;16:1957-67). Of note, this alteration is also designated as 9841GC/CT and 9841_9842GC>CT in published literature. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 15, 2023	This missense variant replaces alanine with leucine at codon 3205 of the BRCA2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least five individuals affected with breast cancer and two individuals affected with prostate cancer and at least two unaffected individuals (PMID: 10717622, 19471317, 20215541, 24728327, 25111659, 25777348, 30883245, 32438681, 33471991; Leiden Open Variation Database DB-ID BRCA2_002741, 35127508, 35402282). This variant has been identified in 6/251370 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. -

Familial cancer of breast Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 09, 2024	ACMG codes applied following ENIGMA VCEP rules: BP1_STR -

not specified Benign:1 Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 06, 2023	Variant summary: BRCA2 c.9613_9614delinsCT (p.Ala3205Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance.c.9613_9614delinsCT has been reported in the literature in individuals affected with a variety of cancers such as breast, ovarian, prostate and/or pancreatic surveillance (example, Sanz_2010, Maier_2014, Malone_2000, El Seghir_2015, Abe_2019, Santonocito_2020, Patruno_2021, Zografos_2022, Bisgin_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least two co-occurrences with other pathogenic variant(s) have been observed at our laboratory (CDH1 c.382delC, p.His128Ilefs; BRCA1 c.2475delC, p.Asp825fsX21), providing supporting evidence for a benign role. At least one publication reports experimental evidence reporting no damaging effect of this variant on splicing in patient lymphocytes (Sanz_2010). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (likely benign, n=1; VUS, n=5). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign. -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

May 03, 2013

- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Ala3205Leu variant was identified by Malone (2000) in a study of young women diagnosed with breast cancer, and was also identified in HGMD, in UMD (1X as an unclassified variant), and in the BIC database (6X with unknown clinical importance). The p.Ala3205 residue in not conserved in mammals and lower organisms, and computational analyses (PolyPhen2, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein; however, this information is not very predictive of pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

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: rs276174926; hg19: chr13-32971146;