ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.1128T>G (p.Ser376Arg)

gnomAD frequency: 0.00003  dbSNP: rs587780204
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000116062 SCV000149971 uncertain significance not provided 2019-11-05 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Invitae RCV000204740 SCV000260002 uncertain significance Familial cancer of breast 2023-09-29 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 376 of the PALB2 protein (p.Ser376Arg). This variant is present in population databases (rs587780204, gnomAD 0.007%). 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: 128116). 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. 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.
Counsyl RCV000204740 SCV000489388 uncertain significance Familial cancer of breast 2016-09-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000568625 SCV000664781 uncertain significance Hereditary cancer-predisposing syndrome 2022-04-22 criteria provided, single submitter clinical testing The p.S376R variant (also known as c.1128T>G), located in coding exon 4 of the PALB2 gene, results from a T to G substitution at nucleotide position 1128. The serine at codon 376 is replaced by arginine, an amino acid with dissimilar properties. This alteration was detected in 2/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000568625 SCV001735487 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-22 criteria provided, single submitter clinical testing This missense variant replaces serine with arginine at codon 376 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/31402 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.
Fulgent Genetics, Fulgent Genetics RCV002483189 SCV002791874 uncertain significance Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3 2021-09-07 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000204740 SCV004019698 uncertain significance Familial cancer of breast 2023-03-31 criteria provided, single submitter clinical testing This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics RCV000204740 SCV004201996 uncertain significance Familial cancer of breast 2023-10-27 criteria provided, single submitter clinical testing

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