Submissions for variant NM_024675.4(PALB2):c.557A>T (p.Asn186Ile)

dbSNP: rs587782164

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130756	SCV000185647	likely benign	Hereditary cancer-predisposing syndrome	2023-08-23	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.
Invitae	RCV000197454	SCV000255111	likely benign	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000197454	SCV000267987	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
GeneDx	RCV000588642	SCV000565342	uncertain significance	not provided	2022-11-18	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with endometrial cancer but also in cancer-free controls (Thompson et al., 2015; Ring et al., 2016); Published functional studies suggest no damaging effect: did not significantly affect PALB2 homology-directed repair function (Brnich et al., 2021); This variant is associated with the following publications: (PMID: 26283626, 27443514, 30638972, 20871615, 19369211, 33964450)
Color Diagnostics, LLC DBA Color Health	RCV000130756	SCV000690937	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 186 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 an individual affected endometrial cancer (PMID: 27443514) and in a breast cancer case-control meta-analysis in 0/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_011164). This variant has been identified in 1/251436 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	RCV000588642	SCV000699606	uncertain significance	not provided	2016-05-16	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.557A>T (p.Asn186Ile) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (Mutation taster and SNPs&GO not captured due to low reliability index). This variant was found in 2/125398 control chromosomes at a frequency of 0.0000159, which does not exceed the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). To our knowledge, the variant was not reported in affected individuals and in vivo/vitro functional studies assessing the impact the variant may have on PALB2 function were not published at the time of scoring either. In an internal sample, the variant was observed to co-occur with a pathogenic PALB2 variant indicating neutrality. Clinical diagnostic laboratories databases classified this variant as Uncertain. Considering all evidence, the variant was classified as a VUS-possibly benign until more information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588642	SCV001134557	uncertain significance	not provided	2019-12-31	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478396	SCV002779140	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-12-25	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315411	SCV004015180	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 5	2023-07-07	criteria provided, single submitter	clinical testing	A variant of uncertain significance was detected in the PALB2 gene (c.557A>T). This sequence change replaces asparagine with isoleucine at codon 186 of the PALB2 protein (p.Asn186Ile). In-silico predictions show benign computational verdict based on 9 benign predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL, LIST-S2, MVP, MutationTaster and PrimateAI vs 3 pathogenic predictions from M-CAP, MutationAssessor and SIFT and the position is not highly conserved. This variant is present in population databases (rs587782164, ExAC 0.01%). This variant has been reported in the literature in an individual affected with endometrial cancer (PMID: 27443514) as well as in an unaffected control individual (PMID: 26283626). ClinVar contains an entry for this variant (Variation ID: 141993) with 7 submissions all of which describe this variant as of uncertain significance. Therefore, it has been classified as a Variant of Uncertain Significance. Genetic counseling is recommended.