Submissions for variant NM_024675.4(PALB2):c.928A>G (p.Ser310Gly)

gnomAD frequency: 0.00001  dbSNP: rs45561331

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212782	SCV000150024	uncertain significance	not provided	2023-12-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast, ovarian, and other cancers; however, it has also been observed in control populations (PMID: 25186627, 32546565, 26315354, 17200668, 29641532); This variant is associated with the following publications: (PMID: 25186627, 26315354, 29641532, 17200668, 32546565, 19369211)
Ambry Genetics	RCV000116115	SCV000186474	likely benign	Hereditary cancer-predisposing syndrome	2022-12-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200242	SCV000255115	uncertain significance	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 310 of the PALB2 protein (p.Ser310Gly). This variant is present in population databases (rs45561331, gnomAD 0.01%). This missense change has been observed in individual(s) with ovarian cancer, familial breast cancer (PMID: 17200668, 26315354). ClinVar contains an entry for this variant (Variation ID: 128149). 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 with a negative 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 (Invitae). 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	RCV000200242	SCV000785788	uncertain significance	Familial cancer of breast	2017-11-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116115	SCV000910851	benign	Hereditary cancer-predisposing syndrome	2016-11-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212782	SCV001470590	uncertain significance	not provided	2020-01-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001290583	SCV001478666	uncertain significance	not specified	2021-01-31	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.928A>G (p.Ser310Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251176 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.00016), allowing no conclusion about variant significance. c.928A>G has been reported in the literature in individuals affected with breast cancer, serous ovarian cancer and unaffected controls (example, Rahman_2007, Ramus_2015, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome or Fanconi Anemia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6; Benign, n=1). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149811	SCV003838090	uncertain significance	Breast and/or ovarian cancer	2022-02-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000200242	SCV004019643	likely benign	Familial cancer of breast	2023-03-31	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].
PreventionGenetics, part of Exact Sciences	RCV004528810	SCV004107303	uncertain significance	PALB2-related disorder	2023-02-23	criteria provided, single submitter	clinical testing	The PALB2 c.928A>G variant is predicted to result in the amino acid substitution p.Ser310Gly. This variant has been reported in an individual with breast cancer and an individual with melanoma (Table S3, Pritchard et al. 2018. PubMed ID: 29641532; Supplement, Tung et al. 2015. PubMed ID: 25186627). It has also been reported in cases and controls from an ovarian cancer cohort study (Ramus et al. 2015. PubMed ID: 26315354). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23646939-T-C). It is interpreted as uncertain significance by the majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/128149/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Leiden Open Variation Database	RCV000200242	SCV001193042	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354315	SCV001548901	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 p.Ser310Gly variant was identified in 5 of 11880 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer or epithelial ovarian cancer and was present in 4 of 9030 control chromosomes (frequency: 0.0004) from healthy individuals (Rahman 2007, Ramus 2015, Tung 2015). The variant was also identified in dbSNP (ID: rs45561331) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and Counsyl), MutDB, LOVD 3.0 (1x), and in the Zhejiang University Database (1x). The variant was not identified in Cosmic database. The variant was identified in control databases in 12 of 246074 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 12 of 111596 chromosomes (freq: 0.0001), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Ser310 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.