rs276174926

Variant names:

• chr13-32397009-GC-CT
• rs276174926
• NM_000059.4:c.9613_9614delGCinsCT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. 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. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.0000239 in 6 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3205T) has been classified as Uncertain significance.

• Frequency: GnomAD MNV: 𝑓 0.000024 Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:5 O:1
• Conservation: PhyloP100: 0.310
• Publications: 11 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• 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 VariationId is 52875.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	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 rank	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	Exon 25 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1671_*1672delGCinsCT		3_prime_UTR_variant	Exon 25 of 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

GnomAD MNV AF: 0.0000239 AC: 6 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Mar 22, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9613_9614delinsCT (p.Ala3205Leu) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 35402282 (2022), 33471991 (2021), 25777348 (2015), 10717622 (2000)), prostate cancer (PMID: 25111659 (2014)), and pancreatic cancer (PMID: 34034685 (2021)). It has also been observed in reportedly healthy individuals (PMIDs: 33471991 (2021), 30883245 (2019), 24728327 (2014)). In addition, this variant has been reported to cause minimal exon 26 skipping in the BRCA2 gene (PMID: 20215541 (2010)). The frequency of this variant in the general population, 0.000026 (3/113676 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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. -

Nov 21, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Nov 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2023

Department of Medical and Surgical Sciences, University of Bologna

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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) -

Jun 06, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:1 Benign:1

Jul 17, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Apr 16, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 09, 2024

MGZ Medical Genetics Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG codes applied following ENIGMA VCEP rules: BP1_STR -

Feb 16, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Jan 02, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.This variant is a multi nucleotide variant (combination of 13-32971146-G-C and 13-32971147-C-T). Both of these variants individually was found at a frequency of 2.4e-05 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). The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 25382762, 35753294, 24728327, 21120943, 25777348, 25111659, 10717622, 34572941, 32438681, 20215541, 36011273, 15365999). ClinVar contains an entry for this variant (Variation ID: 52875). Based on the evidence outlined above, the variant was classified as likely benign. -

Breast and/or ovarian cancer Uncertain:1

May 03, 2013

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Malignant tumor of breast Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.31

Splicing

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

Other links and lift over

dbSNP: rs276174926; hg19: chr13-32971146; COSMIC: COSV107497041;