ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.841A>T (p.Ile281Phe)

gnomAD frequency: 0.00001  dbSNP: rs751882053
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000198379 SCV000255114 uncertain significance Familial cancer of breast 2023-07-31 criteria provided, single submitter clinical testing 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 216761). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is present in population databases (rs751882053, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 281 of the PALB2 protein (p.Ile281Phe).
Ambry Genetics RCV000454145 SCV000538181 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-23 criteria provided, single submitter clinical testing The p.I281F variant (also known as c.841A>T), located in coding exon 4 of the PALB2 gene, results from an A to T substitution at nucleotide position 841. The isoleucine at codon 281 is replaced by phenylalanine, an amino acid with highly similar properties. 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.
Counsyl RCV000198379 SCV000785037 uncertain significance Familial cancer of breast 2017-03-24 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000454145 SCV001356267 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-18 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with phenylalanine at codon 281 of the PALB2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant was identified in 1/60465 cases and 0/53461 controls (PMID: 33471991 - Leiden Open Variation Database DB-ID PALB2_011117). This variant has been identified in 2/251410 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.
Sema4, Sema4 RCV000454145 SCV002531229 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-28 criteria provided, single submitter curation
GeneDx RCV003114361 SCV003798625 uncertain significance not provided 2022-08-03 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 breast cancer and not observed in controls (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 19369211, 33471991)
Myriad Genetics, Inc. RCV000198379 SCV004019119 uncertain significance Familial cancer of breast 2023-03-30 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 RCV000198379 SCV004202154 uncertain significance Familial cancer of breast 2023-07-29 criteria provided, single submitter clinical testing

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