Submissions for variant NM_007294.4(BRCA1):c.4031A>G (p.Asp1344Gly)

gnomAD frequency: 0.00001  dbSNP: rs55639854

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000048411	SCV000076424	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132350	SCV000187439	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-06	criteria provided, single submitter	clinical testing	The p.D1344G variant (also known as c.4031A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 4031. The aspartic acid at codon 1344 is replaced by glycine, an amino acid with similar properties. In a study of 40 Cypriot families with breast and/or ovarian cancer, this variant was detected in one family and was not seen in controls (Hadjisavvas A et al. Cancer Genet. Cytogenet. 2004 Jun; 151(2):152-6). This alteration co-occurred with BRCA2 c.7879A>T in a Macednonian individual affected with breast cancer (Jakimovska M et al. Breast Cancer Res. Treat., 2018 Apr;168:745-753). This alteration also co-occurred with a BRCA1 c.442-34C>T variant in a male patient diagnosed with breast cancer (Vaca-Paniagua F et al. PLoS ONE, 2012 May;7:e37432). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000586179	SCV000293466	likely benign	not provided	2019-04-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 15172753, 16267036, 29335924, 27882536, 22655046, 33087888)
Color Diagnostics, LLC DBA Color Health	RCV000132350	SCV000683144	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 1344 of the BRCA1 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 at least three individuals affected with breast or ovarian cancer and one unaffected individual (PMID: 15172753, 22655046, 33471991; Leiden Open Variation Database DB-ID BRCA1_005338). This variant also has been reported with a family history likelihood ratio for pathogenicity of 0.2217 (PMID: 31131967). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987342	SCV000699098	uncertain significance	not specified	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4031A>G (p.Asp1344Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.5e-06 in 1613526 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4031A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Hadjisavvas_2004, Judkins_2005, Vaca-Paniagua_2012, Loizidou_2017, Jakimovska_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One co-occurrence with another pathogenic variant has been reported (BRCA2 c.7879A>T, p.Ile2627Phe), providing supporting evidence for a benign role (Jakimovska_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15172753, 29335924, 16267036, 27882536, 33087888, 23704879, 22655046). ClinVar contains an entry for this variant (Variation ID: 55077). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000112227	SCV000785945	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-01-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586179	SCV001470172	uncertain significance	not provided	2023-08-28	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in multiple individuals with hereditary breast/ovarian cancer (PMIDs: 15172753 (2004), 16267036 (2005), 22655046 (2012), 26287763 (2015), and 27882536 (2016)). It was also seen in two individuals with breast cancer as well as in a control individual in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). The variant has been described as likely benign in a recent multifactorial likelihood study (PMID: 31131967 (2019)), and was reported to co-occur with a pathogenic BRCA2 variant (PMID: 29335924 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132350	SCV003848744	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
All of Us Research Program, National Institutes of Health	RCV000112227	SCV004817722	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 1344 of the BRCA1 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 at least three individuals affected with breast or ovarian cancer and one unaffected individual (PMID: 15172753, 22655046, 33471991; Leiden Open Variation Database DB-ID BRCA1_005338). This variant also has been reported with a family history likelihood ratio for pathogenicity of 0.2217 (PMID: 31131967). This variant has not been identified 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.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112227	SCV000144937	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing