ClinVar Miner

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

dbSNP: rs749602688
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Total submissions: 6
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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.

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