chr16-23638084-G-C
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_024675.4(PALB2):āc.94C>Gā(p.Leu32Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000768 in 1,613,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_024675.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251478Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
GnomAD4 exome AF: 0.0000821 AC: 120AN: 1461708Hom.: 0 Cov.: 30 AF XY: 0.0000715 AC XY: 52AN XY: 727158
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74348
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 18, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 27, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Published functional studies demonstrate PARPi sensitivity and BRCA1 interaction comparable to wildtype (PMID: 31586400); Observed in individuals with personal or family history of breast, ovarian, and other cancers, as well as in unaffected controls (PMID: 23448497, 25503501, 26283626, 25186627, 25980754, 27153395, 28779002, 33471991, 34687117); This variant is associated with the following publications: (PMID: 24728327, 27425854, 23448497, 25980754, 26283626, 25503501, 25186627, 28779002, 27153395, 28259476, 20871615, 19369211, 33471991, 31586400, 34687117) - |
Uncertain significance, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 20, 2022 | BP4 - |
Hereditary cancer-predisposing syndrome Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 06, 2024 | 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; Lerner-Ellis J et al. J Cancer Res Clin Oncol 2021 Mar;147(3):871-879). 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 reportedly detected in conjunction with a TP53 pathogenic mutation in an individual with early-onset breast cancer (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 16, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 10, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Oct 15, 2024 | The missense variant NM_024675.4(PALB2):c.94C>G (p.Leu32Val) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Leu32Val variant is observed in 1/16,254 (0.0062%) alleles from individuals of gnomAD African background in gnomAD. The p.Leu32Val variant is novel (not in any individuals) in 1kG. There is a small physicochemical difference between leucine and valine, which is not likely to impact secondary protein structure as these residues share similar properties. For these reasons, this variant has been classified as Uncertain Significance. - |
Familial cancer of breast Uncertain:1Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 06, 2016 | - - |
Likely benign, criteria provided, single submitter | case-control | Cancer Genetics Laboratory, Peter MacCallum Cancer Centre | Jun 01, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 23, 2025 | - - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | This variant is considered 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]. 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. - |
not specified Uncertain:1Benign:1Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 24, 2021 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 23, 2024 | 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 7.7e-05 in 1606898 control chromosomes, predominantly at a frequency of 0.0001 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is somewhat lower than the estimated maximum expected for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00016), allowing no conclusion about variant significance. However, the variant was also reported in 2/7325 European American women, who were older than age 70, and have never had cancer (in the FLOSSIES database). The variant, c.94C>G, has been reported in the literature in individuals affected with breast cancer, and other tumor phenotypes, but was also found in several controls (e.g. (e.g. Maxwell_2015, Teo_2013, Thompson_2015, Tung_2015, Yurgelun_2015, Dorling_2021, Sylvester_2022, Tsyganov_2023). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with another pathogenic variant has been reported (TP53 c.733G>A, p.G245S; Maxwell_2015), providing supporting evidence for a benign role. Furthermore, another study reported the variant in a 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). At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated the variant protein had similar activity to the wild-type (Rodrigue_2019). The following publications have been ascertained in the context of this evaluation (PMID: 27153395, 25503501, 31586400, 23448497, 26283626, 25186627, 25980754, 33471991, 34687117, 37628606). ClinVar contains an entry for this variant (Variation ID: 126781). Based on the evidence outlined above, the variant was classified as likely benign. - |
PALB2-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 25, 2024 | The PALB2 c.94C>G variant is predicted to result in the amino acid substitution p.Leu32Val. This variant was identified in an individual suspected of having Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). It has also been identified in several individuals affected with breast cancer (Teo et al. 2013. PubMed ID: 23448497; Table S1, Maxwell et al. 2015. PubMed ID: 25503501; Table S4, Maxwell et al. 2016. PubMed ID: 27153395; Thompson et al. 2015. PubMed ID: 26283626; supplementary data, Tung et al. 2015. PubMed ID: 25186627). However, no further information was provided regarding its pathogenicity or segregation with disease in families. This variant was also identified in a healthy individual with no history of cancer (Table S1, Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/126781/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Fanconi anemia complementation group N Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | 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. - |
Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3;C5830615:Breast-ovarian cancer, familial, susceptibility to, 5 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 07, 2024 | - - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at