Submissions for variant NM_024675.4(PALB2):c.109C>A (p.Arg37Ser)

gnomAD frequency: 0.00006  dbSNP: rs200048921

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV000234405	SCV003915549	uncertain significance	Familial cancer of breast	2023-04-05	reviewed by expert panel	curation	The c.109C>A variant in PALB2 is a missense variant predicted to cause substitution of arginine by serine at amino acid 37 (p.Arg37Ser). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00012 in the African population (PM2_Supporting, BS1, and BA1 are not met). This variant is functional in multiple different protein assays (PMID: 31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. PALB2, in which the variant was identified, is defined by the HBOP VCEP as a gene for which primarily truncating variants are known to cause disease. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BP1)
Ambry Genetics	RCV000164472	SCV000215117	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-22	criteria provided, single submitter	clinical testing	The p.R37S variant (also known as c.109C>A), located in coding exon 3 of the PALB2 gene, results from a C to A substitution at nucleotide position 109. This variant impacts the first base pair of coding exon 3. The arginine at codon 37 is replaced by serine, an amino acid with dissimilar properties. This alteration was found to be functionally normal in DNA-repair assays (Wiltshire T et al. Genet. Med. 2020 03;22:622-632; Brnich SE et al. J Mol Diagn. 2021 07;23:847-864). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234405	SCV000290802	uncertain significance	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 37 of the PALB2 protein (p.Arg37Ser). This variant is present in population databases (rs200048921, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 28194609). ClinVar contains an entry for this variant (Variation ID: 185108). 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. Experimental studies have shown that this missense change does not substantially affect PALB2 function (PMID: 31636395, 33964450). 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	RCV000234405	SCV000489524	uncertain significance	Familial cancer of breast	2016-10-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000656933	SCV000565339	uncertain significance	not provided	2023-07-26	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Lerner-Ellis et al., 2017; Hauke et al., 2018); Published functional studies demonstrate no significant impact on HDR activity (Wiltshire et al., 2020; Brnich et al., 2021); This variant is associated with the following publications: (PMID: 33195396, 33964450, 20871615, 19369211, 36139699, 28194609, 29522266, 34522520, 31636395)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481543	SCV000601723	uncertain significance	not specified	2017-05-18	criteria provided, single submitter	clinical testing
Mendelics	RCV000164472	SCV000839060	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164472	SCV001355420	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 37 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. Two functional studies have reported that this variant does not impact BRCA1 function in homology-directed repair assays (PMID: 31636395, 33964450). This variant has been reported in an individual affected with breast cancer (PMID: 28194609) and a suspected hereditary breast and ovarian cancer family (PMID: 29522266). This variant has been identified in 4/251456 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000481543	SCV001774642	uncertain significance	not specified	2021-07-17	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.109C>A (p.Arg37Ser) results in a non-conservative amino acid change located in the coiled coil domain (Boonen_2020) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251456 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.109C>A has been reported in the literature in at-least one individual affected with ER positive, HER negative breast cancer (example, Lerner-Ellis_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least two publications report primary experimental evidence evaluating an impact on protein function (example, Wiltshire_2020, Brnich_2021 and reviewed in Boonen_2020). These results showed no damaging effect of this variant on homology directed repair activity (Wiltshire_2019) and an intermediate assay read out on homology directed repair function (Brnich_2021). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000234405	SCV004019125	likely benign	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000234405	SCV004202058	uncertain significance	Familial cancer of breast	2023-10-03	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656933	SCV001954460	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000656933	SCV001972338	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004724955	SCV005339599	uncertain significance	PALB2-related disorder	2024-05-16	no assertion criteria provided	clinical testing	The PALB2 c.109C>A variant is predicted to result in the amino acid substitution p.Arg37Ser. This variant was reported in two patients with breast or ovarian cancer (Lerner-Ellis et al. 2017. PubMed ID: 28194609; Hauke et al. 2018. PubMed ID: 29522266). Functional studies are inconclusive regarding the effect of this variant (Wiltshire et al. 2019. PubMed ID: 31636395; Brnich et al. 2021. PubMed ID: 33964450). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. The variant has conflicting classifications in ClinVar, though most submissions classify the variant as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/185108/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.