Submissions for variant NM_024675.4(PALB2):c.2743G>A (p.Ala915Thr)

gnomAD frequency: 0.00003  dbSNP: rs374736398

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129474	SCV000184244	likely benign	Hereditary cancer-predisposing syndrome	2018-12-29	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	RCV000471567	SCV000550663	uncertain significance	Familial cancer of breast	2024-08-29	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 915 of the PALB2 protein (p.Ala915Thr). This variant is present in population databases (rs374736398, gnomAD 0.006%). 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: 141109). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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	RCV000481045	SCV000565353	uncertain significance	not provided	2023-08-21	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 an individual with colorectal cancer and in both cases and controls in a breast cancer study (Yurgelun et al., 2017; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 33471991, 24485656, 19609323, 20871615, 28135145)
Color Diagnostics, LLC DBA Color Health	RCV000129474	SCV000903803	likely benign	Hereditary cancer-predisposing syndrome	2015-12-10	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481045	SCV002046762	uncertain significance	not provided	2021-03-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129474	SCV002530720	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-09	criteria provided, single submitter	curation
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV003315231	SCV004012962	uncertain significance	Diffuse midline glioma, H3 K27-altered	2022-04-28	criteria provided, single submitter	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355149	SCV001549943	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	PALB2, EXON07, c.2743G>A, p.Ala915Thr, Heterozygous, Uncertain Significance The PALB2 p.Ala915Thr variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs374736398) as With Uncertain significance allele, ClinVar (classified as likely benign by Ambry Genetics; classified as uncertain significance by Invitae, GeneDx), Clinvitae (conflicting interpretations of pathogenicity), databases. The variant was identified in control databases in 6 of 246250 chromosomes at a frequency of 0.000024 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Ala915 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The variant is located with the WD40-repeat-containing domain functional domain increasing the likelihood that it may have clinical significance. 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.
GenomeConnect - Invitae Patient Insights Network	RCV004545873	SCV004228514	not provided	PALB2-related disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-27-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.