NM_000059.4(BRCA2):c.68-1G>A AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Dec 16, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000059.4(BRCA2):c.68-1G>A]


BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000013.11:g.32319076G>A
  • NG_012772.3:g.8597G>A
  • NG_017006.2:g.1288C>T
  • NM_000059.4:c.68-1G>AMANE SELECT
  • LRG_293t1:c.68-1G>A
  • LRG_293:g.8597G>A
  • NC_000013.10:g.32893213G>A
  • NM_000059.3:c.68-1G>A
dbSNP: rs1060502376
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000059.4:c.68-1G>A - splice acceptor variant - [Sequence Ontology: SO:0001574]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000665128Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Sep 20, 2019)
germlineclinical testing

Citation Link,

SCV001340511Color Health, Inccriteria provided, single submitter
Uncertain significance
(Dec 16, 2019)
germlineclinical testing

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


This variant is located in intron 2 of the BRCA2 gene. It is predicted to abolish the intron 2 splice acceptor site at the AG dinucleotide at the 3' terminus of the intron. However, there is an alternative AG dinucleotide at c.72_73, which if used is predicted to cause a 6-basepair deletion (r.68_73del) and an in-frame deletion of 2 amino acids. To our knowledge, this variant has not been investigated in any published RNA study nor has this variant been reported in individuals affected with hereditary cancer. Although there is a suspicion that this variant may be associated with disease, the role of this variant in disease cannot be determined conclusively due to the uncertain impact on RNA splicing and the lack of clinical data. Therefore, this variant is classified as a Variant of Uncertain Significance.


Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

Details of each submission

From Ambry Genetics, SCV000665128.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided


The c.68-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 2 of the BRCA2 gene.This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV001340511.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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