Submissions for variant NM_024675.4(PALB2):c.3464C>G (p.Ser1155Cys)

gnomAD frequency: 0.00003  dbSNP: rs755609496

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000454280	SCV000538172	likely benign	Hereditary cancer-predisposing syndrome	2022-02-10	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.
GeneDx	RCV000480681	SCV000573714	uncertain significance	not provided	2025-01-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36993649, 24686850, 19609323, 24485656, 20871615, 32884827, 38110397)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529716	SCV000633436	uncertain significance	Familial cancer of breast	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1155 of the PALB2 protein (p.Ser1155Cys). This variant is present in population databases (rs755609496, gnomAD 0.03%). 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: 402308). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV000454280	SCV000686040	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 1155 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 breast cancer, who has a BRCA2 mobile element insertion, c.7666_7667insSVA, that is suspected to be the causal variant (PMID: 32884827). This variant has been identified in 8/251474 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000480681	SCV004222344	uncertain significance	not provided	2023-03-17	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00026 (8/30616 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 32884827 (2020)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.