rs397507697

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM4_Supporting

The NM_000059.4(BRCA2):c.3900_3902delGAC(p.Met1300_Thr1301delinsIle) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,553,890 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000078 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 0.670

Publications

3 publications found

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 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

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_000059.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.3900_3902delGAC	p.Met1300_Thr1301delinsIle	disruptive_inframe_deletion	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
BRCA2	ENST00000380152.8 link	c.3900_3902delGAC	p.Met1300_Thr1301delinsIle	disruptive_inframe_deletion	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7 link	c.3531_3533delGAC	p.Met1177_Thr1178delinsIle	disruptive_inframe_deletion	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2 link	n.3900_3902delGAC		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000149

AC:

AN:

200696

AF XY:

0.0000182

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000513

Gnomad NFE exome

AF:

0.0000213

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000785

AC:

AN:

1401614

Hom.:

AF XY:

0.00000576

AC XY:

AN XY:

693940

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30768

American (AMR)

AF:

0.00

AC:

AN:

32974

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23904

East Asian (EAS)

AF:

0.00

AC:

AN:

38872

South Asian (SAS)

AF:

0.00

AC:

AN:

76886

European-Finnish (FIN)

AF:

0.000116

AC:

AN:

51546

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5450

European-Non Finnish (NFE)

AF:

0.00000461

AC:

AN:

1083424

Other (OTH)

AF:

0.00

AC:

AN:

57790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.530

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41568

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68002

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000126

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:3

Jan 11, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant causes an in-frame deletion of Met1300 and Thr1301 and the insertion of isoleucine in exon 11 located in the BRCA2 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in an individual affected with ovarian cancer (PMID: 11180606) and in a family affected with breast and/or ovarian cancer (PMID: 22762150). This variant has been identified in 7/232092 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. -

Mar 02, 2020

BRCAlab, Lund University

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 18, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided

Uncertain:2

Nov 01, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In-frame deletion of 2 amino acid(s) and insertion of 1 different amino acid(s) in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Also known as 4128_4130delGAC; This variant is associated with the following publications: (PMID: 22762150, 11180606, 36900197, 35534704, Bahsi2020[case report]) -

Dec 14, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRCA2 c.3900_3902del (p.Met1300_Thr1301delinsIle) variant has been reported in the published literature in individuals with ovarian cancer (PMID: 11180606 (2001)), breast cancer (PMID: 22762150 (2012), an aggressive parathyroid neoplasm (PMID: 36900297 (2023)), and an unspecified cancer (PMID: 35534704 (2022)). The frequency of this variant in the general population, 0.00013 (3/22978 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. " -

Hereditary cancer-predisposing syndrome

Uncertain:2

Sep 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.3900_3902delGAC variant (also known as p.M1300_T1301delinsI) is located in coding exon 10 of the BRCA2 gene. This variant results from an in-frame GAC deletion at nucleotide positions 3900 to 3902. The methionine ant threonine residues at codons 1300 and 1301 are deleted and are replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in a French breast and/or ovarian cancer family (Lecarpentier J et al. Breast Cancer Res. 2012 Jul 3;14(4):R99). The amino acid region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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. -

Oct 29, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant causes an in-frame deletion of Met1300 and Thr1301 and the insertion of isoleucine in exon 11 located in the BRCA2 protein. A functional study has reported the mutant protein to be functional based on the ability to rescue the lethality of Brca2-null mouse embryonic stem cells, as well as sensitivity to multiple DNA damaging agents and PARP inhibitor (PMID: 33293522). This variant has been observed in individuals affected with breast or ovarian cancer (PMID: 11180606, doi.org/10.1515/tjb-2019-0424) and in a family affected with breast and/or ovarian cancer (PMID: 22762150). Multifactorial analyses have reported likelihood ratios (LR) for pathogenicity based on co-occurrence with a pathogenic variant and personal and family history for three carriers, reaching a combined LR of 3.1388 (PMID: 31131967, 31853058). This variant has been identified in 7/232092 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. -

not specified

Uncertain:1

Nov 01, 2018

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA2 c.3900_3902delGAC (p.Met1300_Thr1301delinsIle) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 2.6e-05 in 228420 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3900_3902delGAC has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Demange_2001, Lecarpentier_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.5030_5033delCTAA, p.Thr1677IlefsX2 via UMD), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary breast ovarian cancer syndrome

Uncertain:1

Nov 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.3900_3902del, is a complex sequence change that results in the deletion of 2 and insertion of 1 amino acid(s) in the BRCA2 protein (p.Met1300_Thr1301delinsIle). This variant is present in population databases (rs397507697, gnomAD 0.02%). This variant has been observed in individual(s) with breast cancer, atypical parathyroid tumor (PMID: 11180606, 22762150, 23096105, 35534704). However, in one of these individuals a pathogenic allele was identified in the BRCA1 gene, which suggests that this c.3900_3902del change in BRCA2might not be the primary cause of disease in this individual. This variant is also known as "4128del3" and "M1306I, T1307del". ClinVar contains an entry for this variant (Variation ID: 51555). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.67

Mutation Taster

=87/113

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over