Submissions for variant NM_024675.4(PALB2):c.353T>C (p.Ile118Thr)

gnomAD frequency: 0.00001  dbSNP: rs370404126

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212774	SCV000150016	uncertain significance	not provided	2023-05-24	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; This variant is associated with the following publications: (PMID: 27783279, 24584348, 28779002, 26283626, 30287823, 32980694, 33471991)
Ambry Genetics	RCV000116107	SCV000183975	likely benign	Hereditary cancer-predisposing syndrome	2021-09-15	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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000211074	SCV000267984	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Counsyl	RCV000211074	SCV000489098	uncertain significance	Familial cancer of breast	2016-08-18	criteria provided, single submitter	clinical testing
Invitae	RCV000211074	SCV000550722	uncertain significance	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 118 of the PALB2 protein (p.Ile118Thr). This variant is present in population databases (rs370404126, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 128143). 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 threonine 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.
Color Diagnostics, LLC DBA Color Health	RCV000116107	SCV000904040	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 118 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. In three breast cancer case-control studies, this variant has been observed in 0/1996 BC cases and 1/1998 controls (PMID: 26283626), 0/7051 cases and 1/11241controls (PMID: 30287823), and 5/60466 cases and 1/53461 controls (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010538). In a pancreatic cancer case-control study, this variant has been observed in 0/1005 and 1/23705 controls (PMID: 32980694). This variant has been identified in 3/250634 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	RCV002222397	SCV002500834	uncertain significance	not specified	2022-03-03	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.353T>C (p.Ile118Thr) 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 2.1e-05 in 288088 control chromosomes (gnomAD, publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.353T>C has been reported in the literature in individuals affected with Breast Cancer (Dorling_2021, Decker_2017), however these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One co-occurrence with another pathogenic variant has been seen in our laboratory (CHEK2 c.1100delC, p.Thr367MetfsX15), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: all have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000211074	SCV004019677	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered 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]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Leiden Open Variation Database	RCV000212774	SCV001192966	uncertain significance	not provided	2018-10-10	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.