Submissions for variant NM_024675.4(PALB2):c.3306C>G (p.Ser1102Arg)

dbSNP: rs515726112

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216794	SCV000277108	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-17	criteria provided, single submitter	clinical testing	The p.S1102R variant (also known as c.3306C>G), located in coding exon 12 of the PALB2 gene, results from a C to G substitution at nucleotide position 3306. The serine at codon 1102 is replaced by arginine, an amino acid with dissimilar properties. This variant has been identified in a high-risk Ashkenazi Jewish breast/ovarian cancer family (Catucci I et al, Fam. Cancer 2012 Sep; 11(3):483-91), in a Chinese familial breast cancer proband (Li YT et al. Eur. J. Med. Res. 2015 Oct;20:85), in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535), and in a patient with esophageal squamous cell carcinoma from Iran (Akbari MR et al. Hum Genet, 2011 May;129:573-82). In addition, this alteration was found to be functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet Med, 2020 03;22:622-632). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114615	SCV000633419	uncertain significance	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1102 of the PALB2 protein (p.Ser1102Arg). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with colorectal cancer, esophageal squamous cell carcinoma, and/or a personal or family history of breast cancer (PMID: 21279724, 22692731, 26489409, 27573125, 33980423; Invitae). ClinVar contains an entry for this variant (Variation ID: 126731). 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: 31586400, 31636395). Studies have shown this missense change is associated with skipping of exon 12, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 30890586; 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.
Color Diagnostics, LLC DBA Color Health	RCV000216794	SCV000686028	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 1102 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 reported in individuals affected with breast cancer (PMID: 27573125, 33471991, 33980423). This variant has been identified in 2/251476 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.
Counsyl	RCV000114615	SCV000785279	uncertain significance	Familial cancer of breast	2017-06-27	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000216794	SCV000822116	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000216794	SCV002531165	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267854	SCV002551629	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267854	SCV003844292	uncertain significance	not specified	2023-02-27	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3306C>G (p.Ser1102Arg) results in a non-conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) 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 8e-06 in 251476 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3306C>G has been reported in the literature in individuals affected with Breast Cancer (Catucci_2012, Li_2015, Cecener_2016, EceSolmaz_PALB2_CBC_2021, etc.) and esophageal squamous cell carcinoma (ESCC) (Akbari_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Prostate Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal activity (Wiltshire_2020, Rodrigue_2019). Eight ClinVar submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance (n=8). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000114615	SCV004019706	uncertain significance	Familial cancer of breast	2023-03-31	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	RCV000114615	SCV004202097	uncertain significance	Familial cancer of breast	2023-09-05	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000114615	SCV001193391	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.