ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2422G>A (p.Gly808Arg)

dbSNP: rs1064795507
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486954 SCV000571383 uncertain significance not provided 2017-10-10 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.2422G>A at the cDNA level, p.Gly808Arg (G808R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant was observed in at least one individual with colorectal cancer (Yurgelun 2017). PALB2 Gly808Arg was not observed in large population cohorts (Lek 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Gly808Arg occurs at a position that is not conserved and is located in a region required for interaction with POLH and POLH DNA synthesis stimulation (Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PALB2 Gly808Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV000698122 SCV000826765 uncertain significance Familial cancer of breast 2023-03-28 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). 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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function. ClinVar contains an entry for this variant (Variation ID: 422025). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 808 of the PALB2 protein (p.Gly808Arg).
Color Diagnostics, LLC DBA Color Health RCV000775954 SCV000910460 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-17 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 808 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Ambry Genetics RCV000775954 SCV002737400 uncertain significance Hereditary cancer-predisposing syndrome 2020-05-11 criteria provided, single submitter clinical testing The p.G808R variant (also known as c.2422G>A), located in coding exon 5 of the PALB2 gene, results from a G to A substitution at nucleotide position 2422. The glycine at codon 808 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in a cohort of 1058 patients with colorectal cancer (Yurgelun MB et al. J. Clin. Oncol., 2017 Apr;35:1086-1095). This amino acid position is poorly 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.
Baylor Genetics RCV000698122 SCV005053933 uncertain significance Familial cancer of breast 2023-12-24 criteria provided, single submitter clinical testing

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