Submissions for variant NM_024675.4(PALB2):c.2188A>G (p.Ile730Val)

dbSNP: rs1060502735

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468216	SCV000550608	uncertain significance	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 730 of the PALB2 protein (p.Ile730Val). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 410110). 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.
GeneDx	RCV000479293	SCV000568129	uncertain significance	not provided	2024-07-18	criteria provided, single submitter	clinical testing	Observed in a cohort of individuals with prostate cancer (PMID: 36922933); 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: 22941656, 33471991, 36922933)
Ambry Genetics	RCV000563382	SCV000665135	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	The p.I730V variant (also known as c.2188A>G), located in coding exon 5 of the PALB2 gene, results from an A to G substitution at nucleotide position 2188. The isoleucine at codon 730 is replaced by valine, an amino acid with highly similar properties. This variant was reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Color Diagnostics, LLC DBA Color Health	RCV000563382	SCV000910282	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199879	SCV001370630	uncertain significance	not specified	2020-05-14	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2188A>G (p.Ile730Val) results in a conservative amino acid change in the encoded protein sequence. Five 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 251490 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2188A>G in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been reported (ATM c.1564_1565delGA, p.Glu522IlefsX43; internal sample), providing supporting evidence for a benign role. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV000468216	SCV004202078	uncertain significance	Familial cancer of breast	2023-09-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001199879	SCV005090201	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354437	SCV001549053	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Ile730Val variant was not identified in the literature nor was it identified in the dbSNP database. The variant was identified in ClinVar (classified as uncertain significance by Invitae, GeneDx, and Ambry Genetics). The variant was identified in control databases in 1 of 246268 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111716 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ile730 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.