ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2861A>G (p.Glu954Gly)

dbSNP: rs375942535
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000635705 SCV000757126 uncertain significance Familial cancer of breast 2024-07-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 954 of the PALB2 protein (p.Glu954Gly). This variant is present in population databases (rs375942535, gnomAD 0.0009%). 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: 530081). 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 with a negative predictive value of 80%. 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 RCV000771431 SCV000903796 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-16 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with glycine at codon 954 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. In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 1/53461 unaffected controls, showing inconclusive association with disease (OR= 2.653 (95%CI 0.276 to 25.502); p-value=0.628; Leiden Open Variation Database DB-ID PALB2_010824) (PMID: 33471991). This variant has been identified in 1/251368 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.
Ambry Genetics RCV000771431 SCV001177809 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-14 criteria provided, single submitter clinical testing The p.E954G variant (also known as c.2861A>G), located in coding exon 9 of the PALB2 gene, results from an A to G substitution at nucleotide position 2861. The glutamic acid at codon 954 is replaced by glycine, an amino acid with similar properties. 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.
GeneDx RCV001775933 SCV002013733 uncertain significance not provided 2024-01-28 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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32091409, 24485656, 19609323, 20871615)
Fulgent Genetics, Fulgent Genetics RCV002492979 SCV002783139 uncertain significance Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3 2021-12-14 criteria provided, single submitter clinical testing
Baylor Genetics RCV000635705 SCV004202177 uncertain significance Familial cancer of breast 2023-07-10 criteria provided, single submitter clinical testing

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