ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2821A>G (p.Ile941Val)

gnomAD frequency: 0.00001  dbSNP: rs778602038
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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 RCV000534984 SCV000633379 uncertain significance Familial cancer of breast 2023-12-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 941 of the PALB2 protein (p.Ile941Val). This variant is present in population databases (rs778602038, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 28828701, 33558524). ClinVar contains an entry for this variant (Variation ID: 460961). 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 expected to disrupt PALB2 protein function with a positive 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.
Ambry Genetics RCV000572648 SCV000663316 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-08 criteria provided, single submitter clinical testing The p.I941V variant (also known as c.2821A>G), located in coding exon 8 of the PALB2 gene, results from an A to G substitution at nucleotide position 2821. The isoleucine at codon 941 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in different cancer cohorts and in controls (Mandelker D. et al. JAMA. 2017;318(9):825-835; Hauke J. et al. Cancer Med. 2018;7(4):1349-1358; Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). This alteration was also identified in 1/68 non-Jewish Israeli individuals determined to be at high-risk for breast/ovarian cancer (Zidan J et al. Breast Cancer Res Treat, 2017 Dec;166:881-885).This amino acid position is highly 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 RCV000572648 SCV000685983 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-28 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 941 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 observed in an individual affected with bilateral breast cancer with positive family history of breast cancer (PMID: 33558524), as well as in two individuals affected with breast cancer in a case-control study (PMID: 33471991). This variant has been identified in 5/250838 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759902 SCV000889588 uncertain significance not provided 2021-05-03 criteria provided, single submitter clinical testing
GeneDx RCV000759902 SCV002044263 uncertain significance not provided 2022-10-27 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 individuals with breast, ovarian, or colon cancer (Zidan et al., 2017; Moradian et al., 2021); This variant is associated with the following publications: (PMID: 28828701, 33558524, 28873162, 19609323, 20871615, 24485656)
Fulgent Genetics, Fulgent Genetics RCV002490998 SCV002807001 uncertain significance Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3 2022-02-12 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000759902 SCV004698357 likely benign not provided 2023-12-01 criteria provided, single submitter clinical testing PALB2: BP4
Center of Medical Genetics and Primary Health Care RCV000534984 SCV000987280 uncertain significance Familial cancer of breast 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria PM1 Pathogenic Moderate: WD40 repeat-like (V872-1185 aa) domain, which serves as platform for the assembly of protein complexes (e.g., BRCA1 / RAD51) or mediators of transient interplay among other proteins. Hot spot has 283 non-VUS coding variants (146 pathogenic and 137 benign), pathogenicity = 51.6% > threshold 17.2%. PM2 Pathogenic Moderate: GnomAD exomes allele frequency = 0.0000199 < 0.0001 threshold for recessive gene PALB2. Variant not found in GnomAD genomes. PP3 Pathogenic Supporting: 8 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, MutationAssessor, MutationTaster, SIFT, PolyPhen-2, Align-GVGD vs 5 benign predictions from DEOGEN2, M-CAP, MVP, PrimateAI and REVEL. PP4 Pathogenic Supporting: Female patient was diagnosed with bilateral breast cancer at the age of 55 y.o. with strong family history of breast cancer. 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.

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