Submissions for variant NM_024675.4(PALB2):c.2903C>G (p.Ala968Gly)

gnomAD frequency: 0.00002  dbSNP: rs369132015

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131197	SCV000186147	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-07	criteria provided, single submitter	clinical testing	The p.A968G variant (also known as c.2903C>G), located in coding exon 9 of the PALB2 gene, results from a C to G substitution at nucleotide position 2903. The alanine at codon 968 is replaced by glycine, an amino acid with similar properties. This variant has been detected in multiple breast cancer cohorts (Hauke J et al. Cancer Med, 2018 04;7:1349-1358; Girard E et al. Int J Cancer, 2019 04;144:1962-1974; Dorling et al. N Engl J Med. 2021 02;384:428-439), but has also been identified in a cohort of control patients without breast cancer (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration has also been identified in pancreatic cancer patients undergoing multigene panel testing (Shindo K et al. J Clin Oncol, 2017 Oct;35:3382-3390; Hu H et al. J Am Coll Surg, 2020 11;231:527-535.e14). This amino acid position is 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.
GeneDx	RCV001704012	SCV000279130	likely benign	not provided	2019-05-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 28767289, 22241545, 25980754, 30303537)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114574	SCV000290855	uncertain significance	Familial cancer of breast	2025-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 968 of the PALB2 protein (p.Ala968Gly). This variant is present in population databases (rs369132015, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, pancreatic cancer, and/or suspected Lynch syndrome (PMID: 22241545, 25980754, 28767289, 30303537). ClinVar contains an entry for this variant (Variation ID: 126695). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PALB2 protein function with a positive predictive value of 80%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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	RCV000131197	SCV000685989	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 968 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). A structural modeling study has predicted that this variant may affect PALB2 protein structure (PMID: 34092963). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in three individuals affected with breast cancer (PMID: 22241545, 29522266, 30303537), in one individual affected with pancreatic cancer (PMID: 28767289) and one individual each affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). In a large breast cancer case-control study, this variant has been observed in 2/60464 cases and 2/53459 controls (OR=0.884 (95%CI 0.125 to 6.277); p-value=1) (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010132). This variant has been identified in 8/282862 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.
Mendelics	RCV000114574	SCV001139994	uncertain significance	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000215879	SCV001448391	uncertain significance	not specified	2020-11-06	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2903C>G (p.Ala968Gly) results in a non-conservative amino acid change located in the WD40 domain (IPR031920) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251472 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2903C>G has been reported in the literature in individuals with breast cancer (example, Tischkowitz_2012, Girard_2019), as a VUS in individuals undergoing Lynch syndrome testing (Yurgelun_2015), as a VUS in an individual with PDAC (Shindo_2017) These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5, likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000215879	SCV004027063	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000114574	SCV004202032	uncertain significance	Familial cancer of breast	2024-03-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001704012	SCV004222322	uncertain significance	not provided	2023-05-31	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 22241545 (2012), 29522266 (2018), 30303537 (2019)), ovarian cancer (PMID: 2546565 (2021)), pancreatic cancer (PMID: 32659497 (2020), 28767289 (2017)) and a Lynch syndrome associated cancer (PMID: 25980754 (2015)). In a large-scale breast cancer association study, the variant was observed in breast cancer cases as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/PALB2)). The frequency of this variant in the general population, 0.000054 (7/129178 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV000114574	SCV005898695	benign	Familial cancer of breast	2024-10-30	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. 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].
Leiden Open Variation Database	RCV000114574	SCV001193312	uncertain significance	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
GenomeConnect, ClinGen	RCV004545746	SCV002075110	not provided	PALB2-related disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 12-04-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
PreventionGenetics, part of Exact Sciences	RCV004545746	SCV005361396	uncertain significance	PALB2-related disorder	2024-04-25	no assertion criteria provided	clinical testing	The PALB2 c.2903C>G variant is predicted to result in the amino acid substitution p.Ala968Gly. This variant has been reported in single cases of pancreatic ductal adenocarcinoma, Lynch syndrome, and breast cancer (Shindo et al. 2017. PubMed ID: 28767289; Yurgelun et al. 2015. PubMed ID: 25980754; Tischkowitz et al. 2012. PubMed ID: 22241545; Girard et al. 2019. PubMed ID: 30303537, Table S3). However, the c.2903C>G variant was interpreted as uncertain in one report (Shindo et al. 2017. PubMed ID: 28767289). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126695/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.