ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.212-2A>G (rs730881879)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213220 SCV000277096 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000213220 SCV000537626 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-22 criteria provided, single submitter clinical testing
Counsyl RCV000206312 SCV000677809 likely pathogenic Familial cancer of breast 2015-08-17 criteria provided, single submitter clinical testing
GeneDx RCV000160830 SCV000211503 likely pathogenic not provided 2018-04-23 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.212-2A>G or IVS3-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 3 of the PALB2 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant was identified in at least one individual with breast cancer (Susswein 2015). Based on the current evidence, we consider PALB2 c.212-2A>G to be likely pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000206312 SCV000919928 likely pathogenic Familial cancer of breast 2018-12-14 criteria provided, single submitter clinical testing Variant summary: PALB2 c.212-2A>G 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: Five predict the variant abolishes a 3 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.6e-06 in 217494 control chromosomes. c.212-2A>G has been reported in the literature in one individual affected with Breast Cancer (Susswein_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000206312 SCV000261091 likely pathogenic Familial cancer of breast 2018-12-16 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the PALB2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs730881879, ExAC 0.002%). This variant has been reported in an individual affected with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182757). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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