Submissions for variant NM_024675.4(PALB2):c.583A>G (p.Ile195Val)

dbSNP: rs760784181

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215618	SCV000275562	likely benign	Hereditary cancer-predisposing syndrome	2022-05-11	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.
Color Diagnostics, LLC DBA Color Health	RCV000215618	SCV000908507	likely benign	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001234307	SCV001406945	uncertain significance	Familial cancer of breast	2024-12-28	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 195 of the PALB2 protein (p.Ile195Val). This variant is present in population databases (rs760784181, gnomAD 0.07%). This missense change has been observed in individual(s) with breast cancer or pancreatic cancer (PMID: 28779002, 36175305). ClinVar contains an entry for this variant (Variation ID: 231652). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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.
GeneDx	RCV001030160	SCV001803485	uncertain significance	not provided	2019-11-08	criteria provided, single submitter	clinical testing	While protein-based in silico analysis supports that this variant does not alter protein structure/function, splice predictors suggest this variant may impact gene splicing. In the absence of RNA or functional studies, the actual effect of this sequence change is unknown.; Observed in individuals with breast cancer (Decker 2017); This variant is associated with the following publications: (PMID: 28779002)
Sema4, Sema4	RCV000215618	SCV002531206	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-03	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV005016591	SCV005646500	uncertain significance	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5	2024-03-13	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV001030160	SCV001192990	uncertain significance	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Andreas Laner.