Submissions for variant NM_024675.4(PALB2):c.438A>C (p.Arg146Ser)

gnomAD frequency: 0.00001  dbSNP: rs587781498

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129467	SCV000184237	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	The p.R146S variant (also known as c.438A>C), located in coding exon 4 of the PALB2 gene, results from an A to C substitution at nucleotide position 438. The arginine at codon 146 is replaced by serine, an amino acid with dissimilar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This variant has also been identified in breast cancer cases (Dorling et al. N Engl J Med. 2021 02;384:428-439; Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000212775	SCV000211545	uncertain significance	not provided	2024-07-30	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; This variant is associated with the following publications: (PMID: 28492532, 28779002, 30638972, 19369211, 20871615, 33471991, 29641532, 34326862)
Counsyl	RCV000410126	SCV000489229	uncertain significance	Familial cancer of breast	2016-09-06	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410126	SCV000633451	uncertain significance	Familial cancer of breast	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 146 of the PALB2 protein (p.Arg146Ser). This variant is present in population databases (rs587781498, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 30638972, 34326862). ClinVar contains an entry for this variant (Variation ID: 141105). 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 tolerated. 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	RCV000129467	SCV000911470	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 146 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 (PMID: 28779002) and in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_011181). This variant has been identified in 1/251358 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.
Sema4, Sema4	RCV000129467	SCV002531198	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-09	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212775	SCV002774673	uncertain significance	not provided	2021-08-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410126	SCV004019695	likely benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].