rs786202063

Positions:

chr13-32379843-CTAAAAG-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM4

The NM_000059.4(BRCA2):c.9052_9057delAGTAAA(p.Ser3018_Lys3019del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.0000118 in 1,613,580 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S3018S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 conservative_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:1

Conservation

PhyloP100: 6.71

Variant links:

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 links:

BRCA2 (HGNC:):

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000059.4.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.9052_9057delAGTAAA	p.Ser3018_Lys3019del	conservative_inframe_deletion	23/27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.9052_9057delAGTAAA	p.Ser3018_Lys3019del	conservative_inframe_deletion	23/27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 linkuse as main transcript	c.8683_8688delAGTAAA	p.Ser2895_Lys2896del	conservative_inframe_deletion	23/27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.1110_1115delAGTAAA		non_coding_transcript_exon_variant	22/26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259.2 linkuse as main transcript	n.1110_1115delAGTAAA		3_prime_UTR_variant	22/26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250472

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135410

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461410

Hom.:

AF XY:

0.00000825

AC XY:

AN XY:

727016

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000945

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 19, 2024	Observed in individuals with a personal and/or family history of BRCA2-related cancers and in a pediatric patient with osteosarcoma (PMID: 21918853, 26580448, 29061375, 38069422); In silico analysis supports a deleterious effect on protein structure/function; In-framed deletion of 2 amino acids in a repetitive region; Also known as 9280_9285delAGTAAA; This variant is associated with the following publications: (PMID: 26580448, 21918853, 28243543, 31131967, 29061375, 31853058, 38069422, 12228710, 37216690) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 27, 2024	The BRCA2 c.9052_9057del (p.Lys3019_Ser3020del) variant has been reported in individuals with breast cancer (PMID: 37415649 (2023), 21918853 (2012)) and ovarian cancer (PMID: 38069422 (2023)). In addition, this variant has been identified in a family suspected of having hereditary breast/ovarian cancer (PMID: 29061375 (2018)) and in an individual with osteosarcoma (PMID: 26580448 (2015)). The frequency of this variant in the general population, 0.00032 (8/24908 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 17, 2023	The BRCA2 c.9052_9057del; p.Lys3019_Ser3020del variant (rs786202063), also published as c.9280_9285del; p.3014_3015delSK, is reported in the literature in an individual affected with breast cancer, although its clinical significance was uncertain (de Juan Jimenez 2012). This variant is also reported in ClinVar (Variation ID: 185294). It is found on ten chromosomes (10/281852 alleles) in the Genome Aggregation Database. This variant deletes two amino acids, leaving the rest of the protein in-frame. Due to limited information, the clinical significance of the p.Lys3019_Ser3020del variant is uncertain at this time. References: de Juan Jimenez I et al. Low prevalence of BRCA1 and BRCA2 mutations in the sporadic breast cancer of Spanish population. Fam Cancer. 2012 Mar;11(1):49-56. PMID: 21918853. -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 05, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 02, 2023	This variant results in an in-frame deletion of two amino acids in the BRCA2 protein. This variant is also known as 9280_9285del and p.3014_3015delSK in the literature. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individuals affected with a personal or family history of breast cancer (PMID: 21918853, 35753294). This variant has been identified in 10/281852 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 03, 2021	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. -

Hereditary breast ovarian cancer syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jun 17, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 25, 2023	This variant, c.9052_9057del, results in the deletion of 2 amino acid(s) of the BRCA2 protein (p.Lys3019_Ser3020del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs763756705, gnomAD 0.03%). This variant has been observed in individual(s) with BRCA2-related cancers (PMID: 21918853, 26580448). This variant is also known as c.9280_9285del (p.3014_3015delSK) or S3018_K3019del. ClinVar contains an entry for this variant (Variation ID: 185294). 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. -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 08, 2021

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 24, 2024

Variant summary: BRCA2 c.9052_9057delAGTAAA (p.Lys3019_Ser3020del) results in an in-frame deletion that is predicted to remove two amino acids from the encoded protein. The variant allele was found at a frequency of 2.8e-05 in 250472 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9052_9057delAGTAAA has been reported in the literature in individuals affected with breast cancer (e.g., deJuanJimenez_2021), individuals with a personal or family history of BRCA-related cancer (e.g., Houdayer_2012, Bisgin_2022, Capone_2018), and in a pediatric osteosarcoma case (e.g., Zhang_2015), however without strong evidence for causality. These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Additionally, 4/4 computational tools predict no significant impact on normal splicing, and these predictions are supported by a functional study that found the variant had no effect on splicing at the cDNA level (e.g., Houdayer_2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35753294, 29061375, 22505045, 28243543, 26580448, 21918853). ClinVar contains an entry for this variant (Variation ID: 185294). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Dec 16, 2015

- -

BRCA2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2023

The BRCA2 c.9052_9057del6 variant is predicted to result in an in-frame deletion (p.Lys3019_Ser3020del). This variant is also known as c.9280_9285del (p.3014_3015delSK), has been reported in individuals with breast and/or ovarian cancer (de Juan Jiménez et al. 2012. PubMed ID: 21918853; Capone et al. 2017. PubMed ID: 29061375. Table S1). This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32953980-CTAAAAG-C). In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/185294/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial cancer of breast

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 02, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over