Submissions for variant NM_024675.4(PALB2):c.856C>T (p.Pro286Ser)

gnomAD frequency: 0.00001  dbSNP: rs45585833

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766543	SCV000150022	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in control individuals in a breast cancer case-control study (Rahman et al., 2007); This variant is associated with the following publications: (PMID: 27328445, 19369211, 25085752, 17200668)
Counsyl	RCV000410687	SCV000488631	uncertain significance	Familial cancer of breast	2016-05-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000410687	SCV000550744	uncertain significance	Familial cancer of breast	2024-04-08	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 286 of the PALB2 protein (p.Pro286Ser). This variant is present in population databases (rs45585833, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 17200668, 27328445). ClinVar contains an entry for this variant (Variation ID: 128147). 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 serine 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000766543	SCV000601800	uncertain significance	not provided	2019-04-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000567956	SCV000663295	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	The p.P286S variant (also known as c.856C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 856. The proline at codon 286 is replaced by serine, an amino acid with similar properties. In one study, this alteration was identified in 0/923 familial breast cancer cases and 2/1084 controls (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other 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.
Color Diagnostics, LLC DBA Color Health	RCV000567956	SCV000903855	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-08	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 286 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251406 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174832	SCV001338201	uncertain significance	not specified	2023-03-30	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.856C>T (p.Pro286Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251406 control chromosomes, exclusively observed in 1 female individual within the (non-Finnish) European subpopulation (gnomAD v2.1.1). In addition, the variant was reported in 1 (non-Finnish) European male control individual in gnomAD v3 while, it was also reported in 3/7325 European American women, older than age 70 years, who have never had cancer (FLOSSIES database). Lastly, c.856C>T has been reported in the literature in a familial breast cancer study conducted in Great Britain, where it was found in 2/1084 healthy control individuals (all 48 years of age), and in none of the 923 familial breast cancer cases (Rahman 2007). In summary, this variant has been reported in 7 healthy controls of European descent so far but it has not been reported in patients. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Myriad Genetics, Inc.	RCV000410687	SCV004019693	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].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005394395	SCV006057773	uncertain significance	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5	2024-12-30	criteria provided, single submitter	clinical testing