ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.1646A>G (p.His549Arg)

dbSNP: rs1597095334
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000810610 SCV000950829 uncertain significance Familial cancer of breast 2022-03-19 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 549 of the PALB2 protein (p.His549Arg). ClinVar contains an entry for this variant (Variation ID: 654612). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated.
Ambry Genetics RCV002390633 SCV002704023 uncertain significance Hereditary cancer-predisposing syndrome 2022-06-21 criteria provided, single submitter clinical testing The p.H549R variant (also known as c.1646A>G), located in coding exon 4 of the PALB2 gene, results from an A to G substitution at nucleotide position 1646. The histidine at codon 549 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported as a variant of unknown significance in a Latin American/Caribbean patient with breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Leiden Open Variation Database RCV000810610 SCV001193129 likely benign Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.

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