Submissions for variant NM_024675.4(PALB2):c.292A>G (p.Ile98Val)

gnomAD frequency: 0.00001  dbSNP: rs587782831

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132416	SCV000187508	likely benign	Hereditary cancer-predisposing syndrome	2019-02-22	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.
Invitae	RCV000471839	SCV000550746	uncertain significance	Familial cancer of breast	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 98 of the PALB2 protein (p.Ile98Val). This variant is present in population databases (rs587782831, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 24556926, 31159747). ClinVar contains an entry for this variant (Variation ID: 142935). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
GeneKor MSA	RCV000132416	SCV000822111	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132416	SCV000908516	likely benign	Hereditary cancer-predisposing syndrome	2017-08-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001753518	SCV002005459	uncertain significance	not provided	2019-06-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast cancer as well as healthy controls (Catucci 2014, Momozawa 2018); This variant is associated with the following publications: (PMID: 24556926, 30287823, 31159747)
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225448	SCV002504945	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000471839	SCV001192959	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.