NM_000059.4(BRCA2):c.67+1G>T AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 13, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000045022.19

Allele description [Variation Report for NM_000059.4(BRCA2):c.67+1G>T]

NM_000059.4(BRCA2):c.67+1G>T

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.67+1G>T

HGVS:

NC_000013.11:g.32316528G>T
NG_012772.3:g.6049G>T
NG_017006.2:g.3836C>A
NM_000059.4:c.67+1G>TMANE SELECT
NM_001406719.1:c.67+1G>T
NM_001406720.1:c.67+1G>T
NM_001406721.1:c.67+1G>T
NM_001406722.1:c.-303+861G>T
LRG_293t1:c.67+1G>T
LRG_293:g.6049G>T
NC_000013.10:g.32890665G>T
NM_000059.3:c.67+1G>T
U43746.1:n.295+1G>T

Nucleotide change:

IVS2+1G>T

Links:

Breast Cancer Information Core (BIC) (BRCA2): 295+1&base_change=G to T; dbSNP: rs81002796

NCBI 1000 Genomes Browser:

rs81002796

Molecular consequence:

NM_001406722.1:c.-303+861G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000059.4:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406719.1:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406720.1:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406721.1:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Hereditary breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000073035	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 13, 2023)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 12938098, 29446198, 31706072, 31131967, 17011978, 22505045, 30883759, 20104584, 21203900, 21769658, 24607278, 24916970, 28492532
SCV000694986	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 18, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22505045, 22762150, 12938098, 25342642, 29446198, 30883759 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000073035

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 13, 2023)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

SCV000694986

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 18, 2019)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Clinicopathologic features and genetic characteristics of the BRCA1/2 mutation in Turkish breast cancer patients.

Cecener G, Sabour Takanlou L, Sabour Takanlou M, Egeli U, Eskiler GG, Aksoy S, Unal U, Tezcan H, Eryilmaz IE, Gokgoz MS, Tunca B, Cubukcu E, Evrensel T, Cetintas S, Tasdelen I.

Cancer Genet. 2020 Jan;240:23-32. doi: 10.1016/j.cancergen.2019.10.004. Epub 2019 Oct 16.

PubMed [citation]

PMID:: 31706072

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification.

Parsons MT, Tudini E, Li H, Hahnen E, Wappenschmidt B, Feliubadaló L, Aalfs CM, Agata S, Aittomäki K, Alducci E, Alonso-Cerezo MC, Arnold N, Auber B, Austin R, Azzollini J, Balmaña J, Barbieri E, Bartram CR, Blanco A, Blümcke B, Bonache S, Bonanni B, et al.

Hum Mutat. 2019 Sep;40(9):1557-1578. doi: 10.1002/humu.23818.

PubMed [citation]

PMID:: 31131967
PMCID:: PMC6772163

See all PubMed Citations (15)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000073035.10

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This sequence change affects a donor splice site in intron 2 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and is likely to result in the loss of the initiator methionine. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12938098, 29446198, 31706072). This variant is also known as IVS2+1G>T. ClinVar contains an entry for this variant (Variation ID: 52161). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Studies have shown that disruption of this splice site results in skipping of exon 2, and is expected to result in the loss of the initiator methionine (PMID: 17011978, 22505045, 30883759). This variant disrupts the p.Met1 amino acid residue in BRCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20104584, 21203900, 21769658, 24607278, 24916970). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000694986.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: BRCA2 c.67+1G>T is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict that the variant abolishes a 5 splicing donor site. Experimental evidence demonstrates that this variant affects mRNA splicing by skipping of exon 2 completely (Fraile-Bethencourt_2019, Houdayer_2012). The variant was absent in 250582 control chromosomes (gnomAD). c.67+1G>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Meyer_2003, Rebbeck_2018, Zugazagoitia_2014). These data indicate that the variant is likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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