Submissions for variant NM_024675.4(PALB2):c.2106A>G (p.Ile702Met)

gnomAD frequency: 0.00003  dbSNP: rs730881886

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212805	SCV000211511	uncertain significance	not provided	2023-06-20	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 individuals with a personal or family history including breast and other cancers, as well as in unaffected control groups (Thompson et al., 2015; Lu et al., 2015; Harvey et al., 2017; Hauke et al., 2018; Fujita et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 26283626, 26689913, 29522266, 22941656, 28779002, 33471991, 33309985, 28821472)
Ambry Genetics	RCV000160837	SCV000218024	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	The p.I702M variant (also known as c.2106A>G), located in coding exon 5 of the PALB2 gene, results from an A to G substitution at nucleotide position 2106. The isoleucine at codon 702 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in several cohorts of breast cancer patients and has been absent from controls (Thompson ER et al. Breast Cancer Res, 2015 Aug;17:111; Decker B et al. J Med Genet, 2017 11;54:732-741; Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This variant has also been identified in 1/12503 unselected Japanese colorectal cancer patients and in 0/23705 controls (Fujita M et al. Clin Gastroenterol Hepatol, 2022 Sep;20:2132-2141.e9). 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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000211076	SCV000268007	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Counsyl	RCV000211076	SCV000489066	uncertain significance	Familial cancer of breast	2016-08-11	criteria provided, single submitter	clinical testing
Invitae	RCV000211076	SCV000633330	uncertain significance	Familial cancer of breast	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 702 of the PALB2 protein (p.Ile702Met). This variant is present in population databases (rs730881886, gnomAD 0.002%). This missense change has been observed in individual(s) with head and neck squamous cell carcinoma and breast or ovarian cancer (PMID: 26283626, 26689913, 28821472). ClinVar contains an entry for this variant (Variation ID: 182764). 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 with a negative predictive value of 80%. 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	RCV000160837	SCV000911950	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 702 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 individuals affected with breast cancer, head-neck squamous cell carcinoma and colorectal cancer (PMID: 26283626, 26689913, 28779002, 29522266, 33309985) and in a breast cancer case-control meta-analysis in 2/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010937). This variant has been identified in 3/282882 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.
CeGaT Center for Human Genetics Tuebingen	RCV000212805	SCV002497894	uncertain significance	not provided	2022-01-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160837	SCV002530670	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-17	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000211076	SCV004020276	likely benign	Familial cancer of breast	2023-03-10	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].