ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.94C>G (p.Leu32Val)

gnomAD frequency: 0.00003  dbSNP: rs151316635
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656932 SCV000150026 uncertain significance not provided 2022-08-01 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; Published functional studies demonstrate PARPi sensitivity and BRCA1 interaction comparable to wild type (Rodrigue et al., 2019); Observed in individuals with personal or family history of breast, ovarian, and other cancers, as well as in unaffected controls (Teo et al., 2013; Maxwell et al., 2015; Thompson et al., 2015; Tung et al., 2015; Yurgelun et al., 2015; Maxwell et al., 2016; Decker et al., 2017); This variant is associated with the following publications: (PMID: 24728327, 27425854, 23448497, 25980754, 26283626, 25503501, 25186627, 28779002, 27153395, 28259476, 20871615, 19369211, 31586400, 33471991, 34687117)
Ambry Genetics RCV000116117 SCV000185766 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-30 criteria provided, single submitter clinical testing The p.L32V variant (also known as c.94C>G), located in coding exon 2 of the PALB2 gene, results from a C to G substitution at nucleotide position 94. The leucine at codon 32 is replaced by valine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals diagnosed with breast cancer (Teo ZL et al. Breast Cancer Res. 2013 Feb 28;15:R17). In one study, this alteration was reported in 6/13087 breast cancer cases and 1/5488 control individuals from the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). It was also <span style="font-family:arial,helvetica,sans-serif">reportedly detected in conjunction with a TP53 pathogenic mutation in an individual with early-onset breast cancer<span style="font-family:arial,helvetica,sans-serif"> (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8). <span style="font-family:arial,helvetica,sans-serif">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.
Invitae RCV000114673 SCV000255117 likely benign Familial cancer of breast 2021-12-11 criteria provided, single submitter clinical testing
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114673 SCV000267979 likely benign Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Counsyl RCV000114673 SCV000488135 uncertain significance Familial cancer of breast 2016-01-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656932 SCV000601801 uncertain significance not provided 2020-12-18 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000116117 SCV000902879 likely benign Hereditary cancer-predisposing syndrome 2020-12-10 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001119845 SCV001278291 uncertain significance Fanconi anemia complementation group N 2017-04-28 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121744 SCV001372423 likely benign not specified 2020-06-08 criteria provided, single submitter clinical testing Variant summary: PALB2 c.94C>G (p.Leu32Val) results in a 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 1.6e-05 in 251478 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance (gnomAD). c.94C>G has been reported in the literature in individuals affected with breast cancer and Lynch syndrome but also, in controls (e.g. Maxwell_2015, Teo_2013, Thompson_2015, Tung_2015, Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a TP53 pathogenic variant (c.733G>A, p.G245S) has been reported in a patient with breast cancer (Maxwell_2015). Another study reported the variant in one heterozygous individual at high risk for breast and/or ovarian cancer with a classification of Likely benign, using lack of segregation in affected family members as evidence (Maxwell_2016). Experimental evidence evaluating an impact on protein function demonstrated the variant has similar activity to wild-type (Rodrigue_2019). Altogether, these data provide supporting evidence for a benign role. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; uncertain significance, n=7). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory,University of Chicago RCV000121744 SCV002065318 uncertain significance not specified 2021-05-24 criteria provided, single submitter clinical testing DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.94C>G, in exon 2 that results in an amino acid change, p.Leu32Val. This sequence change has been described in gnomAD with a frequency of 0.004% in the African-American sub-population (dbSNP rs151316635). The p.Leu32Val change affects a moderately conserved amino acid residue located in a domain of the PALB2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu32Val substitution. This sequence change has been reported in multiple individuals affected with breast cancer (PMID: 23448497, 25503501, 26283626). In one study, an individual with early onset breast cancer was also found to be a carrier of a pathogenic TP53 sequence change (PMID: 25503501). Additionally, the PALB2 Leu32Val variant has been identified in two individuals undergoing multigene panel testing due to a history of a Lynch syndrome-related cancer and/or polyps (PMID: 25980754). Functional studies evaluating impact on protein function demonstrated that this variant has similar activity to wild-type (PMID: 31586400). Based on the currently available evidences, the clinical significance of the p.Leu32Val change remains unknown at this time.
Sema4,Sema4 RCV000116117 SCV002531240 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-16 criteria provided, single submitter curation
ITMI RCV000121744 SCV000085942 not provided not specified 2013-09-19 no assertion provided reference population
Leiden Open Variation Database RCV000656932 SCV001192923 uncertain significance not provided 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357251 SCV001552667 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The PALB2 p.Leu32Val variant was identified in 6 of 12886 proband chromosomes (frequency: 0.00047) from individuals or families with breast cancer or Lynch syndrome and was present in 10 of 5358 control chromosomes (frequency: 0.002) from healthy individuals (Maxwell 2015, Teo 2013, Thompson 2015, Tung 2015, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs151316635) as "With Likely benign,other allele ", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Counsyl, GeneDx, PALB2 database and one clinical laboratory; as likely benign by one clinical laboratory) , MutDB , LOVD 3.0 (3x), and in Zhejiang University Database (1x). The variant was not identified in Cosmic, database. The variant was identified in control databases in 5 of 277244 chromosomes at a frequency of 0.000018 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24034 chromosomes (freq: 0.00004), European in 4 of 126730 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu32 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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.

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