Submissions for variant NM_024675.4(PALB2):c.110G>A (p.Arg37His)

gnomAD frequency: 0.00003  dbSNP: rs202194596

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212768	SCV000149970	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history including breast, colorectal, pancreatic, and other cancers (Tischkowitz et al., 2012; Blanco et al., 2013; Decker et al., 2017; Pearlman et al., 2017); This variant is associated with the following publications: (PMID: 27978560, 23935836, 22241545, 28319063, 25428177, 28678401, 28779002, 31757951, 31586400, 31636395, 32209438, 32185139, 33195396, 33169439, 33811135, 33964450, 33139182, 19369211, 20871615)
Ambry Genetics	RCV000116061	SCV000183951	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	The p.R37H variant (also known as c.110G>A), located in coding exon 3 of the PALB2 gene, results from a G to A substitution at nucleotide position 110. The arginine at codon 37 is replaced by histidine, an amino acid with highly similar properties. One study identified this alteration in 1/565 unilateral breast cancer cases and 0/559 bilateral breast cancer cases (Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80). Another study identified this alteration in 1/132 BRCA1/2-negative Spanish breast/ovarian cancer families with at least one case of pancreatic cancer (Blanco A et al. PLoS ONE. 2013 Jul;8:e67538). This variant has also been identified in 1/450 individuals with early onset colorectal cancer and in 1/417 individuals with head and neck squamous cell carcinoma (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Chandrasekharappa SC et al. Cancer. 2017 Oct;123:3943-3954). Functional studies demonstrate that this alteration results in mild reduction in homologous repair activity, but it does not affect PALB2-BRCA1 binding and does not confer sensitivity to platinum therapy, mitomycin C, or olaparib therapy, similar to wild-type (Foo TK et al. Oncogene. 2017 Jul;36:4161-4170). Additional studies have shown that this alteration is functionally normal in a homology-directed DNA repair (HDR) assay (Wiltshire T et al. Genet. Med., 2020 03;22:622-632), but is functionally inconclusive in PARPi sensitivity, cisplatin sensitivity, RAD51 foci formation and BRCA1/2 interaction assays (Boonen RACM et al. Nat Commun, 2019 11;10:5296, Rodrigue A et al. Nucleic Acids Res., 2019 11;47:10662-10677). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is still limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114460	SCV000255073	uncertain significance	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 37 of the PALB2 protein (p.Arg37His). This variant is present in population databases (rs202194596, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, colorectal cancer, and personal or family history of breast and/or ovarian cancer (PMID: 22241545, 23934836, 23935836, 27978560, 28779002, 36175305). ClinVar contains an entry for this variant (Variation ID: 126590). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on PALB2 function (PMID: 28319063, 31586400, 31636395, 31757951, 33139182). 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	RCV000114460	SCV000488531	uncertain significance	Familial cancer of breast	2016-04-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116061	SCV000685851	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 37 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). Functional studies of this variant have demonstrated moderate to low effects on homologous recombination, BRCA1-interaction, RAD51 foci formation, and PARP inhibitor sensitivity (PMID: 28319063, 31586400, 31636395, 31757951, 33195396, 33811135). This variant has been reported in individuals affected with breast, pancreatic, prostate, colorectal and head and neck cancer in the literature (PMID: 22241545, 23935836, 27978560, 28678401, 28779002, 31214711, 33309985, 33471991, 33811135). This variant also has been reported in two individuals unaffected with breast cancer (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010020). This variant has been identified in 11/282840 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	RCV000116061	SCV000839059	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780571	SCV000917960	uncertain significance	not specified	2022-04-01	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.110G>A (p.Arg37His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant is also located at the second exonic base from a canonical 3' splice acceptor site. 5/5 computational tools predict no significant impact on normal splicing, which is supported by a functional study (Blanco_2013). The variant allele was found at a frequency of 4e-05 in 251458 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.00016), allowing no conclusion about variant significance. c.110G>A has been reported in the literature in sequencing studies of individuals from BRCA families with at-least once case of pancreatic cancer (Blanco_2013); Head and Neck Squamous Cell Carcinoma (HNSCC) (Chandrashekarappa_2017); colorectal cancer (Pearlman_2016); and unilateral breast cancer (Tischkowitz_2012). A systematic review summarizing the earlier reports indicated this variant as not having co-segregated with disease along with a predicted pathogenicity assignment of VUS (Zhan_2018). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Several publications report conflicting experimental evidence evaluating an impact on the various protein functions examined. While the most pronounced variant effect results in 30%-50% of normal activity in HDR assays (Rodrigue_2019 and Boonen_2019), conflicting results resulting in 50-90% of normal activity in HDR assays have also been reported (Foo_2017 and Wiltshire_2019). The results from the ability of this variant to recruit PALB2 to DNA damage sites report conflicting findings ranging from no effect (Foo_2017, Rodrigue_2019) versus an impaired effect (estimated at 54% of WT, Boonen_2019). Ability to form RAD51C foci also exhibited inter-assay variability ranging from no effect (Foo_2017) to a slightly compromised level estimated at 71% of WT (Rodrigue_2019). Lastly, moderate but statistically significant levels of sensitivity to PARP inhibitors such as Olaparib were reported in two studies (Rodrigue_2019 and Boonen_2019). In summary, an unequivocal correlation of these experimental reports to the in-vivo impact of this variant cannot be established from the findings reviewed. Seven clinical diagnostic laboratories and the LOVD have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as uncertain significance some citing overlapping evidence utilized in the context of this evaluation. Based on the reviewed evidence outlined above, the variant retained its classification as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212768	SCV001134529	uncertain significance	not provided	2018-12-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002483177	SCV002789413	uncertain significance	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3	2021-12-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114460	SCV004019751	likely benign	Familial cancer of breast	2023-04-03	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].
Baylor Genetics	RCV000114460	SCV004202005	uncertain significance	Familial cancer of breast	2024-03-15	criteria provided, single submitter	clinical testing
Leiden Open Variation Database	RCV000212768	SCV001192930	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.
PreventionGenetics, part of Exact Sciences	RCV004739369	SCV005350852	uncertain significance	PALB2-related disorder	2024-05-09	no assertion criteria provided	clinical testing	The PALB2 c.110G>A variant is predicted to result in the amino acid substitution p.Arg37His. This variant has been observed in individuals with a history of breast/ovarian and colorectal cancer (Blanco et al. 2013. PubMed ID: 23935836; Pearlman et al. 2017. PubMed ID: 27978560). However, it has also been reported in control cohorts (Supplementary Table S1, Tischkowitz et al. 2012. PubMed ID: 22241545). In vitro functional studies support that this variant does not impact BRCA1 protein interactions but does reduce PALB2 homologous recombination repair activity (Foo et al. 2017. PubMed ID: 28319063). This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD and has conflicting interpretation in ClinVar ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/126590/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.