ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.3201+1G>C (rs587776423)

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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 RCV000164723 SCV000215394 pathogenic Hereditary cancer-predisposing syndrome 2017-10-03 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,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without splicing assay data in support of pathogenicity,Other strong data supporting pathogenic classification
Color RCV000164723 SCV000903744 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000133485 SCV000617238 likely pathogenic not provided 2017-03-27 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.3201+1G>C or IVS11+1G>C and consists of a G>C nucleotide substitution at the +1 position of intron 11 of the PALB2 gene. This variant destroys a canonical splice donor 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 has been observed in an individual with bilateral breast cancer (Tischkowitz 2012). Based on the currently available information, we consider PALB2 c.3201+1G>C to be a likely pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000778459 SCV000914710 uncertain significance PALB2-Related Disorders 2017-08-25 criteria provided, single submitter clinical testing The PALB2 c.3201+1G>C variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt or distort the normal gene product. This variant, also referred to as c.3202+1G>C, has been reported in a heterozygous state in one individual with contralateral breast cancer (Tischkowitz et al. 2012), and was absent from 565 controls with unilateral breast cancer. In addition, a variant at the same position, but with a different nucleotide change (c.3201+1G>T) was detected in a heterozygous state in an individual with hereditary diffuse gastric cancer (Sahasrabudhe et al. 2017). Family histories of the respective cancers were also reported for both individuals in first- and/or second- degree relatives (Tischkowitz et al. 2012; Sahasrabudhe et al. 2017). The c.3201+1G>C variant was not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Although the c.3201+1G>C variant has not been reported in the literature in individuals with Fanconi anemia, it cannot be ruled out of causing this condition based on allele frequency in consideration of condition penetrance and prevalence estimates. Based on the evidence and the potential impact of splice donor variants, the c.3201+1G>C variant is classified as a variant of unknown significance but suspicious for pathogenicity for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000230297 SCV000290867 likely pathogenic Familial cancer of breast 2018-09-13 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 11 of the PALB2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 22241545), and in a family included in a study to estimate breast cancer risk (PMID: 25099575). This variant is referred to as c.3202+1G>C in the literature (PMID: 22241545). ClinVar contains an entry for this variant (Variation ID: 143972). 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.
SNPedia RCV000133485 SCV000188559 pathogenic not provided no assertion criteria provided not provided Converted during submission to Pathogenic.

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