Submissions for variant NM_024675.4(PALB2):c.1421G>A (p.Ser474Asn)

dbSNP: rs786201806

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164284	SCV000214911	likely benign	Hereditary cancer-predisposing syndrome	2024-06-20	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	RCV000235242	SCV000293261	uncertain significance	not provided	2024-11-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect (PMID: 31636395); This variant is associated with the following publications: (PMID: 31636395, 32546565, 35843025, 26315354)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000693357	SCV000821223	uncertain significance	Familial cancer of breast	2023-09-27	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 474 of the PALB2 protein (p.Ser474Asn). This variant is present in population databases (rs786201806, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 184941). 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. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395). 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	RCV000164284	SCV001348973	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-21	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000693357	SCV004202713	uncertain significance	Familial cancer of breast	2022-09-21	criteria provided, single submitter	clinical testing