ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.10C>T (p.Pro4Ser)

gnomAD frequency: 0.00001  dbSNP: rs587782483
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131600 SCV000186615 likely benign Hereditary cancer-predisposing syndrome 2024-05-01 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx RCV004696852 SCV000211559 uncertain significance not provided 2024-12-09 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest no impact on homology directed repair activity (PMID: 31757951); This variant is associated with the following publications: (PMID: 20871615, 19369211, 31757951)
Labcorp Genetics (formerly Invitae), Labcorp RCV000205368 SCV000261201 uncertain significance Familial cancer of breast 2024-10-21 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 4 of the PALB2 protein (p.Pro4Ser). This variant is present in population databases (rs587782483, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 142468). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health RCV000131600 SCV000685849 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-05 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 4 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study reported that this variant has nearly wild-type activity in homology-directed DNA repair assay and relative resistance to PARP inhibitor (PMID: 31757951). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/278454 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Counsyl RCV000205368 SCV000786423 uncertain significance Familial cancer of breast 2018-04-27 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000205368 SCV004019670 likely benign Familial cancer of breast 2024-04-09 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics RCV000205368 SCV004202112 uncertain significance Familial cancer of breast 2023-08-25 criteria provided, single submitter clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund RCV004696852 SCV005197098 uncertain significance not provided 2022-06-03 criteria provided, single submitter clinical testing

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