Submissions for variant NM_024675.4(PALB2):c.2753C>A (p.Pro918Gln)

gnomAD frequency: 0.00001  dbSNP: rs587780822

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123341	SCV000166657	uncertain significance	Familial cancer of breast	2025-02-04	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 918 of the PALB2 protein (p.Pro918Gln). This variant is present in population databases (rs587780822, gnomAD 0.02%). This missense change has been observed in individual(s) with gastric cancer (PMID: 28024868). ClinVar contains an entry for this variant (Variation ID: 136136). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PALB2 protein function with a positive 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.
Ambry Genetics	RCV000220315	SCV000275429	likely benign	Hereditary cancer-predisposing syndrome	2021-06-04	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000507163	SCV000601771	uncertain significance	not specified	2016-08-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000220315	SCV000690873	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-18	criteria provided, single submitter	clinical testing	This missense variant replaces proline with glutamine at codon 918 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hereditary diffuse gastric cancer (PMID: 28024868). This variant has been identified in 8/249726 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.
GeneDx	RCV001546031	SCV001765473	uncertain significance	not provided	2023-01-24	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with gastric cancer (Sahasrabudhe et al., 2017); This variant is associated with the following publications: (PMID: 29706558, 24485656, 19609323, 20871615, 28024868)
Sema4, Sema4	RCV000220315	SCV002530721	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-27	criteria provided, single submitter	curation
Baylor Genetics	RCV000123341	SCV005053879	uncertain significance	Familial cancer of breast	2024-02-25	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV001546031	SCV005194280	uncertain significance	not provided		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV004739426	SCV005359872	uncertain significance	PALB2-related disorder	2024-08-26	no assertion criteria provided	clinical testing	The PALB2 c.2753C>A variant is predicted to result in the amino acid substitution p.Pro918Gln. This variant was reported in a mother and daughter who were both diagnosed with gastric cancer (Sahasrabudhe et al. 2017. PubMed ID: 28024868). The p.Pro918Gln residue resides within the WD40 domain that mediates protein binding with BRCA2, RAD51, and RAD51C (Sahasrabudhe et al. 2017. PubMed ID: 28024868). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD and has been classified as a variant of uncertain significance in ClinVar by the vast majority of submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/136136/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.