ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.1181A>T (p.His394Leu)

gnomAD frequency: 0.00001  dbSNP: rs762430363
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV001184922 SCV001351017 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-05 criteria provided, single submitter clinical testing This missense variant replaces histidine with leucine at codon 394 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with acute megakaryoblastic leukemia (PMID: 26580448). This variant has been identified in 2/250950 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001359927 SCV001555816 uncertain significance Familial cancer of breast 2023-12-27 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 394 of the PALB2 protein (p.His394Leu). This variant is present in population databases (rs762430363, gnomAD 0.006%). This missense change has been observed in individual(s) with pancreatic ductal adenocarcinoma (PMID: 35171259). ClinVar contains an entry for this variant (Variation ID: 923898). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PALB2 protein function. 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.
Ambry Genetics RCV001184922 SCV002638220 likely benign Hereditary cancer-predisposing syndrome 2024-05-07 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.
Baylor Genetics RCV001359927 SCV004202108 uncertain significance Familial cancer of breast 2023-08-29 criteria provided, single submitter clinical testing

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