NM_000059.4(BRCA2):c.632-3C>G AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Nov 9, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000220060.19

Allele description [Variation Report for NM_000059.4(BRCA2):c.632-3C>G]

NM_000059.4(BRCA2):c.632-3C>G

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.632-3C>G

HGVS:

NC_000013.11:g.32329440C>G
NG_012772.3:g.18961C>G
NM_000059.4:c.632-3C>GMANE SELECT
LRG_293t1:c.632-3C>G
LRG_293:g.18961C>G
NC_000013.10:g.32903577C>G
NM_000059.3:c.632-3C>G

Nucleotide change:

IVS7-3C>G

Links:

dbSNP: rs568027879

NCBI 1000 Genomes Browser:

rs568027879

Molecular consequence:

NM_000059.4:c.632-3C>G - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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NADH dehydrogenase subunit 6 (mitochondrion) [Manouria emys]
NADH dehydrogenase subunit 6 (mitochondrion) [Manouria emys]
gi|84488772|gnl|NCBI_MITO|ND6_19109 YP_448814.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000278028	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Nov 9, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22505045, 25381700, 30883759, 32123317, 32398771 Citation Link,
SCV001353618	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 19, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002536223	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Likely pathogenic (Sep 11, 2021)	germline	curation	PubMed (6) [See all records that cite these PMIDs] 33466630, 22505045, 30883759, 32123317, 29446198, 31131967 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000278028

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Nov 9, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001353618

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 19, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002536223

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Likely pathogenic
(Sep 11, 2021)

germline

curation

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, curation

Citations

PubMed

Fanconi anemia and solid malignancies in childhood: a national retrospective study.

Malric A, Defachelles AS, Leblanc T, Lescoeur B, Lacour B, Peuchmaur M, Maurage CA, Pierron G, Guillemot D, d'Enghien CD, Soulier J, Stoppa-Lyonnet D, Bourdeaut F.

Pediatr Blood Cancer. 2015 Mar;62(3):463-70. doi: 10.1002/pbc.25303. Epub 2014 Nov 8.

PubMed [citation]

PMID:: 25381700

Alternative mRNA splicing can attenuate the pathogenicity of presumed loss-of-function variants in BRCA2.

Mesman RLS, Calléja FMGR, de la Hoya M, Devilee P, van Asperen CJ, Vrieling H, Vreeswijk MPG.

Genet Med. 2020 Aug;22(8):1355-1365. doi: 10.1038/s41436-020-0814-5. Epub 2020 May 13. Erratum in: Genet Med. 2020 Aug;22(8):1427-1428. doi: 10.1038/s41436-020-0883-5.

PubMed [citation]

PMID:: 32398771
PMCID:: PMC7394881

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000278028.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The c.632-3C>G intronic variant results from a C to G substitution 3 nucleotides upstream from coding exon 7 in the BRCA2 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. This alteration results in use of this novel cryptic acceptor site two nucleotides upstream of the native site resulting in a frameshifting transcript (Ambry internal data; Houdayer C et al. Hum. Mutat. 2012 Aug;33(8):1228-38; Fraile-Bethencourt E et al. J. Pathol., 2019 08;248:409-420). In addition, this alteration has been shown to express an in-frame transcript, known as 6q39_8 in the literature (Ambry internal data). This transcript has been shown to be able to perform homology directed repair in protein functional studies at a near wild-type level (Mesman, RLS et al. Genet Med 2020 08;22(8):1355-1365). This alteration was identified as homozygous in a fetus with features consistent with Fanconi anemia (Malric, A et al. Pediatr Blood Cancer 2015 Mar;62(3):463-70). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

#	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 Color Diagnostics, LLC DBA Color Health, SCV001353618.2

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

Description

This variant causes a C to G nucleotide substitution at the -3 position of intron 7 of the BRCA2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Functional RNA studies have shown that this variant causes the use of an alternative splice acceptor site 2-nucleotide upstream of the reference acceptor site, creating premature translation stop signal in the RNA transcripts (PMID: 22505045, 30883759). The aberrant transcripts are expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 22505045, Color internal data). In addition, a multifactorial likelihood model using health history and tumor pathology data has suggested this variant have a high probability of being pathogenic (PMID: 31131967). This variant has been identified in 1/243142 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely 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 Sema4, Sema4, SCV002536223.1

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

#	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: Oct 26, 2024

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