Submissions for variant NM_024675.4(PALB2):c.2066C>T (p.Ser689Leu)

dbSNP: rs749602688

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228021	SCV000290823	uncertain significance	Familial cancer of breast	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 689 of the PALB2 protein (p.Ser689Leu). This variant is present in population databases (rs749602688, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 26110843, 30287823, 33646313). ClinVar contains an entry for this variant (Variation ID: 241537). 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	RCV000774634	SCV000908480	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 689 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 one individual affected with breast cancer (PMID: 34299313). In multiple case-control studies, this variant has not shown a significant association with breast or pancreatic cancer (PMID: 32980694, 30287823, 33471991 - Leiden Open Variation Database DB-ID PALB2_01045). This variant has been identified in 1/251460 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.
Ambry Genetics	RCV000774634	SCV001174909	likely benign	Hereditary cancer-predisposing syndrome	2018-12-07	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.
Myriad Genetics, Inc.	RCV000228021	SCV004020131	likely benign	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic.
Leiden Open Variation Database	RCV001030274	SCV001193179	uncertain significance	not provided	2018-10-10	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.
PreventionGenetics, part of Exact Sciences	RCV004541455	SCV004800033	uncertain significance	PALB2-related disorder	2024-01-22	no assertion criteria provided	clinical testing	The PALB2 c.2066C>T variant is predicted to result in the amino acid substitution p.Ser689Leu. This variant has been reported in cases and controls from a female breast cancer cohort and was interpreted as uncertain significance (Momozawa et al. 2018. PubMed ID: 30287823, Supp. Data 1). It has also been seen in a single patient with breast cancer (George et al 2021. PubMed ID: 33646313, eTable 3). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/241537/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.