Submissions for variant NM_024675.4(PALB2):c.3415A>G (p.Ile1139Val)

gnomAD frequency: 0.00001  dbSNP: rs1249960937

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001020240	SCV001181693	likely benign	Hereditary cancer-predisposing syndrome	2018-05-10	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001361922	SCV001557915	uncertain significance	Familial cancer of breast	2025-01-22	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 1139 of the PALB2 protein (p.Ile1139Val). This variant is not present in population databases (gnomAD no frequency). 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: 823746). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine 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.
Johns Hopkins Genomics, Johns Hopkins University	RCV001361922	SCV002051781	uncertain significance	Familial cancer of breast	2021-11-16	criteria provided, single submitter	clinical testing
GeneDx	RCV004588497	SCV005078814	uncertain significance	not provided	2024-05-01	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 33195396, 24485656, 19609323, 20871615, 34585473)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004702583	SCV005205171	uncertain significance	not specified	2024-06-17	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3415A>G (p.Ile1139Val) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251468 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3415A>G has been reported in the literature in one individual affected with Fanconi anemia, without strong evidence for causality (George_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34585473). ClinVar contains an entry for this variant (Variation ID: 823746). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356031	SCV001551085	uncertain significance	Familial ovarian cancer		no assertion criteria provided	clinical testing	The PALB2 p.Ile1139Val variant was not identified in the literature nor was it identified in the ClinVar, LOVD 3.0, Exome Aggregation Consortium (August 8th 2016) and Genome Aggregation Database (Feb 27, 2017). The variant was identified in dbSNP (rs1249960937). The p.Ile1139 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 and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a 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.